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Hou L, Guo Y, Xu S, Bai M, Cao W, Zhang Y, Jia Z, Zhang A. HNF3α Targets Nckap1l and Promotes Renal Fibrosis Following Ischemia-Reperfusion Injury. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2410764. [PMID: 40091743 DOI: 10.1002/advs.202410764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 02/20/2025] [Indexed: 03/19/2025]
Abstract
Chronic Kidney Disease (CKD) is a global health challenge, with acute kidney injury (AKI) from ischemia-reperfusion injury (IRI) as a common cause. This study explored the role of Hepatocyte Nuclear Factor 3 alpha (HNF3α/FOXA1) in renal fibrosis and CKD after IRI. Kidney biopsy specimens from CKD patients and mouse models (IRI or unilateral ureteral obstruction) showed HNF3α upregulation in fibrotic kidneys, linked to renal function decline. Additional experiments demonstrated that deletion of HNF3α mitigated IRI-induced renal fibrosis, and that overexpression of HNF3α led to increased fibrosis. Examination of the potential mechanism by transcriptome sequencing and CUT&Tag sequencing suggested that HNF3α promoted renal fibrosis by increasing the expression of the NCK associated protein 1 like (Nckap1l, formerly known as hematopoietic protein 1 [Hem1]), a vital component of the WAVE complex which plays a significant role in cytoskeletal regulation and cell migration. These results underscore the critical function of HNF3α in renal fibrosis following IRI, and also identify Nckap1l as a potential therapeutic target, thus opening new avenues for research and potential therapeutic interventions for CKD and renal fibrosis.
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Affiliation(s)
- Ling Hou
- Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Yan Guo
- Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
- Jiangsu Key Laboratory of Early Development and Chronic Diseases Prevention in Children, Nanjing Medical University, Nanjing, 210029, China
| | - Shuang Xu
- Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
- Jiangsu Key Laboratory of Early Development and Chronic Diseases Prevention in Children, Nanjing Medical University, Nanjing, 210029, China
| | - Mi Bai
- Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
- Jiangsu Key Laboratory of Early Development and Chronic Diseases Prevention in Children, Nanjing Medical University, Nanjing, 210029, China
| | - Weidong Cao
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
- Jiangsu Key Laboratory of Early Development and Chronic Diseases Prevention in Children, Nanjing Medical University, Nanjing, 210029, China
| | - Yue Zhang
- Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
- Jiangsu Key Laboratory of Early Development and Chronic Diseases Prevention in Children, Nanjing Medical University, Nanjing, 210029, China
| | - Zhanjun Jia
- Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
- Jiangsu Key Laboratory of Early Development and Chronic Diseases Prevention in Children, Nanjing Medical University, Nanjing, 210029, China
| | - Aihua Zhang
- Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
- Jiangsu Key Laboratory of Early Development and Chronic Diseases Prevention in Children, Nanjing Medical University, Nanjing, 210029, China
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Li L, Wu YQ, Yang JE. Stress-Related LncRNAs and Their Roles in Diabetes and Diabetic Complications. Int J Mol Sci 2025; 26:2194. [PMID: 40076814 PMCID: PMC11900361 DOI: 10.3390/ijms26052194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 02/23/2025] [Accepted: 02/27/2025] [Indexed: 03/14/2025] Open
Abstract
Diabetes mellitus (DM) is a chronic metabolic disorder and one of the most significant global health burdens worldwide. Key pathophysiological mechanisms underlying its onset and associated complications include hyperglycemia-related stresses, such as oxidative stress and endoplasmic reticulum stress (ER stress). Long non-coding RNAs (lncRNAs), defined as RNA transcripts longer than 200 nucleotides and lacking protein-coding capacity, play crucial roles in various biological processes and have emerged as crucial regulators in the pathogenesis of diabetes. This review provides a comprehensive overview of lncRNA biogenesis and its functional roles, emphasizing recent findings that link stress-related lncRNAs to diabetic pathology and complications. Also, we discuss how lncRNAs influence diabetes and its complications by modulating pathways involved in cell death, proliferation, inflammation, and fibrosis, which contribute to pancreatic β cell dysfunction, insulin resistance, diabetic nephropathy, and retinopathy. By analyzing current research, we aim to enhance understanding of lncRNA involvement in diabetes while identifying potential therapeutic targets and guiding future research directions to elucidate the complex mechanisms underlying this pervasive condition.
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Affiliation(s)
| | | | - Jin-E Yang
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Xin Gang Xi Road 135#, Guangzhou 510275, China; (L.L.); (Y.-Q.W.)
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Zhang C, Zhao H, Yan Y, Li Y, Lei M, Liu Y, Yang L, Zhao H, Zhou S, Pan S, Liu Z, Guo J. LncRNA evf-2 Exacerbates Podocyte Injury in Diabetic Nephropathy by Inducing Cell Cycle Re-entry and Inflammation Through Distinct Mechanisms Triggered by hnRNPU. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2406532. [PMID: 39470303 DOI: 10.1002/advs.202406532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 07/30/2024] [Indexed: 10/30/2024]
Abstract
Albuminuria is a hallmark of diabetic nephropathy (DN). Podocyte injury significantly contributes to proteinuria in DN. Our study found that lncRNA EVF-2 is upregulated in podocytes of DN patients, correlating with cell cycle re-entry and inflammation. Specific knockout or knockdown of lncRNA evf-2 in diabetic mice or cultured podocytes alleviated podocyte injury associated with these processes. RNA sequencing of evf-2-overexpressing podocytes unveiled a predominant enrichment of upregulated mRNAs in cell cycle and inflammation pathways, with alternative splicing in cell cycle-related mRNAs Ccnb1 and Tacc3. Chromatin isolation by RNA purification-mass spectrometry (ChIRP-MS) analysis highlighted the involvement of ribonucleoprotein complex and mRNA processing-related proteins, with hnRNPU as the main binding partner of evf-2 in spliceosomes. Knockdown of hnRNPU partially restored the upregulation of mRNAs induced by evf-2 overexpression, altering splice variants of Ccnb1 and Tacc3. This study is the first to reveal the splice variants of cell cycle-related genes in DN and elucidate the interaction between lncRNA evf-2 and hnRNPU. This interaction culminates in the upregulation of cell cycle-related genes and inflammatory factors through diverse pathways, potentially involving transcriptional activation, RNA stability modulation, alternative splicing or translational regulation. This highlights potential novel pathways for DN treatment.
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Affiliation(s)
- Chaojie Zhang
- Nephrology Research Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, P. R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P. R. China
| | - Hui Zhao
- Nephrology Research Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, P. R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P. R. China
| | - Yufan Yan
- Nephrology Research Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, P. R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P. R. China
| | - Yanfei Li
- Nephrology Research Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, P. R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P. R. China
| | - Min Lei
- Nephrology Research Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, P. R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P. R. China
| | - Yong Liu
- Nephrology Research Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, P. R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P. R. China
| | - Longhua Yang
- School of Pharmaceutical Sciences & Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou University, Henan, 450001, China
| | - Huijian Zhao
- School of Pharmaceutical Sciences & Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou University, Henan, 450001, China
| | - Sijie Zhou
- Nephrology Research Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, P. R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P. R. China
| | - Shaokang Pan
- Nephrology Research Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, P. R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P. R. China
| | - Zhangsuo Liu
- Nephrology Research Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, P. R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P. R. China
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, China
- Innovation Center of Basic Research for Metabolic-Associated Fatty Liver Disease, Ministry of Education of China China
| | - Jia Guo
- Nephrology Research Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, P. R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P. R. China
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, China
- Innovation Center of Basic Research for Metabolic-Associated Fatty Liver Disease, Ministry of Education of China China
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Meng Z, Li T, Li J, Ding S, Liu Y, Zhao G, Chen C, Zhao P, Zhou L. LncRNAPVT1 is Associated with Cancer-Associated Fibroblasts Proliferation Through Regulating TGF-βin Oral Squamous Cell Carcinoma. Immunol Invest 2024; 53:1250-1263. [PMID: 39189542 DOI: 10.1080/08820139.2024.2395874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/28/2024]
Abstract
INTRODUCTION Human oral squamous cell carcinoma (OSCC) is the most common type of oral cancer and has a poor survival rate. Cell-cell communication between OSCC cells and cancer-associated fibroblasts (CAFs) plays important roles in OSCC progression. We previously demonstrated that CAFs promote OSCC cell migration and invasion. However, how OSCC cells influence CAFs proliferation is unknown. METHODS Knockdown of PVT1 was confirmed using lentivirus infection technique. CAFs in tissues were identified by staining the cells with α-SMA using immunohistochemical technique. CCK-8 assay was used to evaluate cell proliferation. The mRNA level of a gene was measured by qRT-PCR. Secreted TGF-β were detected using ELISA assay. RESULTS We found that knockdown of the long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) was associated with a low density of CAFs in xenograft tumors in mice; further analysis revealed that PVT1 in OSCC cells induced CAF proliferation through transforming growth factor (TGF)-β. DISCUSSION Our results demonstrate that lncRNA PVT1 in tumor cells participates in CAF development in OSCC by regulating TGF-β. This study revealed a new mechanism by which PVT1 regulates OSCC progression and PVT1 is a potential therapeutic target in OSCC.
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Affiliation(s)
- Zhen Meng
- Biomedical Laboratory, Medical School of Liaocheng University, Liaocheng, Shandong Province, P.R. China
| | - Tongjuan Li
- Department of Stomatology, Anqiu Municipal Hospital, Weifang, Shandong Province, P.R. China
| | - Jun Li
- Precision Biomedical Laboratory of Liaocheng, Liaocheng People's Hospital, Medical School of Liaocheng University, Liaocheng, Shandong Province, P.R. China
| | - Shuxin Ding
- Department of Oral and Maxillofacial Surgery, Liaocheng People's Hospital, Liaocheng, Shandong Province, P.R. China
- Department of Oral and Maxillofacial Surgery, School of Stomatology, Weifang Medicial University, Weifang, Shandong Province, P.R. China
| | - Yujiao Liu
- Department of Oral and Maxillofacial Surgery, Liaocheng People's Hospital, Liaocheng, Shandong Province, P.R. China
| | - Guoli Zhao
- Department of Pathology, Liaocheng Tumor Hospital, Liaocheng, Shandong Province, P.R. China
| | - Cheng Chen
- Department of Oral and Maxillofacial Surgery, Liaocheng People's Hospital, Liaocheng, Shandong Province, P.R. China
| | - Peng Zhao
- Department of Oral and Maxillofacial Surgery, Liaocheng People's Hospital, Liaocheng, Shandong Province, P.R. China
| | - Longxun Zhou
- Department of Oral and Maxillofacial Surgery, Liaocheng People's Hospital, Liaocheng, Shandong Province, P.R. China
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Lv Z, Wang Z, Hu J, Su H, Liu B, Lang Y, Yu Q, Liu Y, Fan X, Yang M, Shen N, Zhang D, Zhang X, Wang R. LncRNA PVT1 induces mitochondrial dysfunction of podocytes via TRIM56 in diabetic kidney disease. Cell Death Dis 2024; 15:697. [PMID: 39349450 PMCID: PMC11442824 DOI: 10.1038/s41419-024-07107-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 09/19/2024] [Accepted: 09/23/2024] [Indexed: 10/02/2024]
Abstract
Mitochondrial dysfunction is a significant contributor to podocyte injury in diabetic kidney disease (DKD). While previous studies have shown that PVT1 might play a vital role in DKD, the precise molecular mechanisms are largely unknown. By analyzing the plasma and kidney tissues of DKD patients, we observed a significant upregulation of PVT1 expression, which exhibited a positive correlation with albumin/creatinine ratios and serum creatinine levels. Then, we generated mice with podocyte-specific deletion of PVT1 (Nphs2-Cre/Pvt1flox/flox) and confirmed that the deletion of PVT1 suppressed podocyte mitochondrial dysfunction and inflammation in addition to ameliorating diabetes-induced podocyte injury, glomerulopathy, and proteinuria. Subsequently, we cultured podocytes in vitro and observed that PVT1 expression was upregulated under hyperglycemic conditions. Mechanistically, we demonstrated that PVT1 was involved in mitochondrial dysfunction by interacting with TRIM56 post-transcriptionally to modulate the ubiquitination of AMPKα, leading to aberrant mitochondrial biogenesis and fission. Additionally, the release of mtDNA and mtROS from damaged mitochondria triggered inflammation in podocytes. Subsequently, we verified the important role of TRIM56 in vivo by constructing Nphs2-Cre/Trim56flox/flox mice, consistently with the results of Nphs2-Cre/Pvt1flox/flox mice. Together, our results revealed that upregulation of PVT1 could promote mitochondrial dysfunction and inflammation of podocyte by modulating TRIM56, highlighting a potential novel therapeutic target for DKD.
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Affiliation(s)
- Zhimei Lv
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
- Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China
| | - Ziyang Wang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
- Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China
| | - Jinxiu Hu
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
- Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China
| | - Hong Su
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Bing Liu
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Yating Lang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Qun Yu
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Yue Liu
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Xiaoting Fan
- Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China
| | - Meilin Yang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Ning Shen
- Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China
| | - Dongdong Zhang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Xia Zhang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Rong Wang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
- Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China.
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Rong L, Xue H, Hao J, Liu J, Xu H. Long non-coding RNA MEG3 silencing weakens high glucose-induced mesangial cell injury by decreasing LIN28B expression by sponging and sequestering miR-23c. Kidney Res Clin Pract 2024; 43:600-613. [PMID: 38148128 PMCID: PMC11467368 DOI: 10.23876/j.krcp.23.090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 07/18/2023] [Accepted: 07/20/2023] [Indexed: 12/28/2023] Open
Abstract
BACKGROUND Diabetic nephropathy (DN) is a common kidney disease in diabetic patients. Long non-coding RNA maternally expressed gene 3 (MEG3) and microRNA (miR)-23c are reported to be implicated in DN development. Nevertheless, it is unclear that the molecular mechanism between MEG3 and miR-23c in DN remains unclear. METHODS Human mesangial cells (HMCs) were treated with high glucose (HG) to simulate the DN status in vitro. Expression of MEG3 and miR-23c was measured. Effects of MEG3 silencing on HG-stimulated HMC injury were determined. The relationship between MEG3 and miR-23c was verified by the dual-luciferase reporter and RNA immunoprecipitation assays. RESULTS MEG3 was overexpressed in serums from DN patients and HG-stimulated HMCs. MEG3 knockdown weakened HG-stimulated HMC proliferation, extracellular matrix (ECM) accumulation, and inflammation. MEG3 regulated lin-28 homolog B (LIN28B) expression through adsorbing miR-23c. MiR-23c inhibitor reversed MEG3 knockdown-mediated effects on HG-stimulated HMC proliferation, ECM accumulation, and inflammation. LIN28B overexpression overturned miR-23c mimic-mediated effects on HG-stimulated HMC proliferation, ECM accumulation, and inflammation. CONCLUSION MEG3 regulated HMC injury via regulation of the miR-23c/LIN28B axis in DN, which can help us better understand the mechanism of DN mediated by MEG3.
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Affiliation(s)
- Lu Rong
- Department of Urology, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou, China
| | - Huanzhou Xue
- Department of Urology, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou, China
| | - Jianwei Hao
- Department of Urology, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou, China
| | - Jianjun Liu
- Department of Urology, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou, China
| | - Hao Xu
- Department of Urology, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou, China
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Tu X, Zhang H, Ren H. LINC01232 targeting miR-1250-3p/MSH2 axis attenuates mesangial cell proliferation and fibrosis in diabetic nephropathy. Mol Cell Biochem 2024; 479:2093-2103. [PMID: 37642881 DOI: 10.1007/s11010-023-04828-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 08/09/2023] [Indexed: 08/31/2023]
Abstract
The significance of long non-coding RNA (ncRNAs) in the initiation and progression of diabetic nephropathy (DN) has attracted much interest. The purpose of this work was to ascertain the role of LINC01232 in cell models and animal models of DN. C57BL/6 J mice were administered with streptozotocin (STZ) to develop animal models of DN, and mouse glomerular mesangial cells (MCs) were exposed to high glucose (HG) to establish cell models of DN. Expression levels of LINC01232, miR-1250-3p and MSH2 were identified by quantitative real-time PCR (qPCR) or western blotting. Fibrosis-related proteins were quantified by western blotting. MC proliferative capacity was checked by EdU assay. DN progression and fibrosis level in animal models were assessed by hematoxylin and eosin (HE) and Masson staining. The potential binding sites between miR-1250-3p and LINC01232 or MSH2 were examined by dual-luciferase reporter assay. LINC01232 expression was heightened in kidney tissues of DN patients. Its overexpression in HG-treated MCs alleviated MC proliferation and fibrosis. Overexpression of LINC01232 alleviated the pathological state of glomerular hypertrophy, MC hyperplasia, basement membrane thickening, and fibrosis in the DN models. LINC01232 bound to miR-1250-3p and competed for miR-1250-3p binding sites with MSH2. LINC01232 overexpression decoyed miR-1250-3p to increase MSH2 expression, and MSH2 depletion restored LINC01232 overexpression-inhibited MC proliferation and fibrosis. LINC01232 alleviated the mesangial cell proliferation and fibrosis in the progression of DN by targeting miR-1250-3p/MSH2 pathway.
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Affiliation(s)
- Xian Tu
- Nephrology Department, Wuhan Asia General Hospital, Wuhan, 430050, Hubei, China
| | - Hualei Zhang
- Health Check Center, Wuhan Asia General Hospital, No. 300 Taizihu North Road, Economic and Technological Development Zone, Wuhan, 430050, Hubei, China
| | - Hongyan Ren
- Health Check Center, Wuhan Asia General Hospital, No. 300 Taizihu North Road, Economic and Technological Development Zone, Wuhan, 430050, Hubei, China.
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Yang H, Sun J, Sun A, Wei Y, Xie W, Xie P, Zhang L, Zhao L, Huang Y. Podocyte programmed cell death in diabetic kidney disease: Molecular mechanisms and therapeutic prospects. Biomed Pharmacother 2024; 177:117140. [PMID: 39018872 DOI: 10.1016/j.biopha.2024.117140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 06/28/2024] [Accepted: 07/10/2024] [Indexed: 07/19/2024] Open
Abstract
Diabetic kidney disease (DKD) is the primary cause of chronic kidney and end-stage renal disease. Glomerular podocyte loss and death are pathological hallmarks of DKD, and programmed cell death (PCD) in podocytes is crucial in DKD progression. PCD involves apoptosis, autophagy, ferroptosis, pyroptosis, and necroptosis. During DKD, PCD in podocytes is severely impacted and primarily characterized by accelerated podocyte apoptosis and suppressed autophagy. These changes lead to a gradual decrease in podocyte numbers, impairing the glomerular filtration barrier function and accelerating DKD progression. However, research on the interactions between the different types of PCD in podocytes is lacking. This review focuses on the novel roles and mechanisms of PCD in the podocytes of patients with DKD. Additionally, we summarize clinical drugs capable of regulating podocyte PCD, present challenges and prospects faced in developing drugs related to podocyte PCD and suggest that future research should further explore the detailed mechanisms of podocyte PCD and interactions among different types of PCD.
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Affiliation(s)
- Haoyu Yang
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Jun Sun
- Changchun University of Chinese Medicine, Changchun 130117, China
| | - Aru Sun
- Changchun University of Chinese Medicine, Changchun 130117, China
| | - Yu Wei
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Weinan Xie
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Pengfei Xie
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Lili Zhang
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China.
| | - Linhua Zhao
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China.
| | - Yishan Huang
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China; China-Japan Friendship Hospital, Beijing 100029, China.
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Tan RZ, Jia J, Li T, Wang L, Kantawong F. A systematic review of epigenetic interplay in kidney diseases: Crosstalk between long noncoding RNAs and methylation, acetylation of chromatin and histone. Biomed Pharmacother 2024; 176:116922. [PMID: 38870627 DOI: 10.1016/j.biopha.2024.116922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 06/06/2024] [Accepted: 06/09/2024] [Indexed: 06/15/2024] Open
Abstract
The intricate crosstalk between long noncoding RNAs (lncRNAs) and epigenetic modifications such as chromatin/histone methylation and acetylation offer new perspectives on the pathogenesis and treatment of kidney diseases. lncRNAs, a class of transcripts longer than 200 nucleotides with no protein-coding potential, are now recognized as key regulatory molecules influencing gene expression through diverse mechanisms. They modulate the epigenetic modifications by recruiting or blocking enzymes responsible for adding or removing methyl or acetyl groups, such as DNA, N6-methyladenosine (m6A) and histone methylation and acetylation, subsequently altering chromatin structure and accessibility. In kidney diseases such as acute kidney injury (AKI), chronic kidney disease (CKD), diabetic nephropathy (DN), glomerulonephritis (GN), and renal cell carcinoma (RCC), aberrant patterns of DNA/RNA/histone methylation and acetylation have been associated with disease onset and progression, revealing a complex interplay with lncRNA dynamics. Recent studies have highlighted how lncRNAs can impact renal pathology by affecting the expression and function of key genes involved in cell cycle control, fibrosis, and inflammatory responses. This review will separately address the roles of lncRNAs and epigenetic modifications in renal diseases, with a particular emphasis on elucidating the bidirectional regulatory effects and underlying mechanisms of lncRNAs in conjunction with DNA/RNA/histone methylation and acetylation, in addition to the potential exacerbating or renoprotective effects in renal pathologies. Understanding the reciprocal relationships between lncRNAs and epigenetic modifications will not only shed light on the molecular underpinnings of renal pathologies but also present new avenues for therapeutic interventions and biomarker development, advancing precision medicine in nephrology.
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Affiliation(s)
- Rui-Zhi Tan
- Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand; Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Jian Jia
- Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Tong Li
- Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Li Wang
- Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China.
| | - Fahsai Kantawong
- Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand.
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Xie Y, Yuan Q, Tang B, Xie Y, Cao Y, Qiu Y, Zeng J, Wang Z, Su H, Zhang C. CPT1A Protects Podocytes From Lipotoxicity and Apoptosis In Vitro and Alleviates Diabetic Nephropathy In Vivo. Diabetes 2024; 73:879-895. [PMID: 38506804 DOI: 10.2337/db23-0811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 03/12/2024] [Indexed: 03/21/2024]
Abstract
Defective fatty acid oxidation (FAO) has been implicated in diabetic kidney disease (DKD), yet little is known about the role of carnitine palmitoyltransferase-1A (CPT1A), a pivotal rate-limiting enzyme of FAO, in the progression of DKD. Here, we investigate whether CPT1A is a reliable therapeutic target for DKD. We first confirmed the downregulation expression of CPT1A in glomeruli from patients with diabetes. We further evaluated the function of CPT1A in diabetic models. Overexpression of CPT1A exhibited protective effects in diabetic conditions, improving albuminuria and glomerular sclerosis as well as mitigating glomerular lipid deposits and podocyte injury in streptozotocin-induced diabetic mice. Mechanistically, CPT1A not only fostered lipid consumption via fatty acid metabolism pathways, thereby reducing lipotoxicity, but also anchored Bcl2 to the mitochondrial membrane, thence preventing cytochrome C release and inhibiting the mitochondrial apoptotic process. Furthermore, a novel transcription factor of CPT1A, FOXA1, was identified. We elucidate the crucial role of CPT1A in mitigating podocyte injury and the progression of DKD, indicating that targeting CPT1A may be a promising avenue for DKD treatment. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Yajuan Xie
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qian Yuan
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ben Tang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yaru Xie
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yiling Cao
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yang Qiu
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jieyu Zeng
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhiwen Wang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | | | - Chun Zhang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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11
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Wang W, Li Y, Zhu F, Huang Y. STAT3-induced upregulation of lncRNA TTN-AS1 aggravates podocyte injury in diabetic nephropathy by promoting oxidative stress. Toxicol Res (Camb) 2024; 13:tfae079. [PMID: 38828128 PMCID: PMC11142850 DOI: 10.1093/toxres/tfae079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 05/09/2024] [Accepted: 05/17/2024] [Indexed: 06/05/2024] Open
Abstract
Background Diabetic nephropathy (DN) is the most common microvascular complication of diabetes mellitus (DM), being the second cause of end-stage renal disease globally. Podocyte injury is closely associated with DN developmen. Our study aimed to investigate the role of long non-coding RNA (lncRNA) TTN-AS1 in DN-associated podocyte injury. Methods The mouse podocyte cell line (MPC5) and human primary podocytes were stimulated by high glucose (HG; 30 nM glucose) to establish the cellular model of DN. Before HG stimulation, both podocytes were transfected with sh-TTN-AS1#1/2 or pcDNA3.1/STAT3 to evaluate the influence of TTN-AS1 knockdown or STAT3 overexpression on HG-induced podocyte injury. TTN-AS1 and STAT3 expression in both podocytes was examined by RT-qPCR. Cell viability and death were assessed by CCK-8 and LDH release assay. ELISA was adopted for testing IL-6 and TNF-α contents in cell supernatants. The levels of oxidative stress markers (ROS, MDA, SOD, and GSH) in cell supernatants were determined by commercial kits. Western blotting was used for measuring the expression of fibrosis markers (fibronectin and α-SMA and podocyte function markers (podocin and nephrin) in podocytes. Results HG stimulation led to decreased cell viability, increased cell death, fibrosis, inflammation, cell dysfunction and oxidative stress in podocytes. However, knockdown of TTN-AS1 ameliorated HG-induced podocyte injury. Mechanically, the transcription factor STAT3 interacted with TTN-AS1 promoter and upregulated TTN-AS1 expression. STAT3 overexpression offset the protective effect of TTN-AS1 silencing on HG-induced podocyte damage. Conclusion Overall, STAT3-mediated upregulation of lncRNA TTN-AS1 could exacerbate podocyte injury in DN through suppressing inflammation and oxidative stress.
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Affiliation(s)
- Wenzhe Wang
- Department of Nephrology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, No. 26, Shengli Street, Jiang'an District, Wuhan, Hubei 430014, China
| | - Yongxia Li
- Department of Nephrology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, No. 26, Shengli Street, Jiang'an District, Wuhan, Hubei 430014, China
| | - Fan Zhu
- Department of Nephrology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, No. 26, Shengli Street, Jiang'an District, Wuhan, Hubei 430014, China
| | - Yunfang Huang
- Department of Nephrology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, No. 26, Shengli Street, Jiang'an District, Wuhan, Hubei 430014, China
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Huang Z, Pan T, Xu L, Shi L, Ma X, Zhou L, Wang L, Wang J, Zhu G, Chen D, Song L, Pan X, Wang X, Li X, Luo Y, Chen Y. FGF4 protects the liver from immune-mediated injury by activating CaMKK β-PINK1 signal pathway to inhibit hepatocellular apoptosis. Acta Pharm Sin B 2024; 14:1605-1623. [PMID: 38572102 PMCID: PMC10985030 DOI: 10.1016/j.apsb.2023.12.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 12/11/2023] [Accepted: 12/15/2023] [Indexed: 04/05/2024] Open
Abstract
Immune-mediated liver injury (ILI) is a condition where an aberrant immune response due to various triggers causes the destruction of hepatocytes. Fibroblast growth factor 4 (FGF4) was recently identified as a hepatoprotective cytokine; however, its role in ILI remains unclear. In patients with autoimmune hepatitis (type of ILI) and mouse models of concanavalin A (ConA)- or S-100-induced ILI, we observed a biphasic pattern in hepatic FGF4 expression, characterized by an initial increase followed by a return to basal levels. Hepatic FGF4 deficiency activated the mitochondria-associated intrinsic apoptotic pathway, aggravating hepatocellular apoptosis. This led to intrahepatic immune hyper-reactivity, inflammation accentuation, and subsequent liver injury in both ILI models. Conversely, administration of recombinant FGF4 reduced hepatocellular apoptosis and rectified immune imbalance, thereby mitigating liver damage. The beneficial effects of FGF4 were mediated by hepatocellular FGF receptor 4, which activated the Ca2+/calmodulin-dependent protein kinasekinase 2 (CaMKKβ) and its downstream phosphatase and tensin homologue-induced putative kinase 1 (PINK1)-dependent B-cell lymphoma 2-like protein 1-isoform L (Bcl-XL) signalling axis in the mitochondria. Hence, FGF4 serves as an early response factor and plays a protective role against ILI, suggesting a therapeutic potential of FGF4 and its analogue for treating clinical immune disorder-related liver injuries.
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Affiliation(s)
- Zhifeng Huang
- Hepatology Diagnosis and Treatment Center, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Tongtong Pan
- Hepatology Diagnosis and Treatment Center, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China
| | - Liang Xu
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University & Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Medical University, Wenzhou 325035, China
| | - Lu Shi
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China
| | - Liya Zhou
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Luyao Wang
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Jiaojiao Wang
- Hepatology Diagnosis and Treatment Center, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Guoqing Zhu
- Hepatology Diagnosis and Treatment Center, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China
| | - Dazhi Chen
- Hangzhou Medical College, Hangzhou 311300, China
| | - Lingtao Song
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Xiaomin Pan
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Xiaodong Wang
- Hepatology Diagnosis and Treatment Center, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China
| | - Xiaokun Li
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Yongde Luo
- Hepatology Diagnosis and Treatment Center, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Yongping Chen
- Hepatology Diagnosis and Treatment Center, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China
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Shelke V, Kale A, Sankrityayan H, Anders HJ, Gaikwad AB. Long non-coding RNAs as emerging regulators of miRNAs and epigenetics in diabetes-related chronic kidney disease. Arch Physiol Biochem 2024; 130:230-241. [PMID: 34986074 DOI: 10.1080/13813455.2021.2023580] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 12/22/2021] [Indexed: 01/19/2023]
Abstract
Diabetes is one of the major cause of chronic kidney disease (CKD), including "diabetic nephropathy," and is an increasingly prevalent accelerator of the progression of non-diabetic forms of CKD. The long non-coding RNAs (lncRNAs) have come into the limelight in the past few years as one of the emerging weapons against CKD in diabetes. Available data over the past few years demonstrate the interaction of lncRNAs with miRNAs and epigenetic machinery. Interestingly, the evolving data suggest that lncRNAs play a vital role in diabetes-associated CKD by regulation of epigenetic enzymes such as DNA methyltransferase, histone deacetylases, and histone methyltransferases. LncRNAs are also engaged in the regulation of several miRNAs in diabetic nephropathy. Hence this review will elaborate on the association between lncRNAs and their interaction with epigenetic regulators involved in different aspects and thus the progression of CKD in diabetes.
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Affiliation(s)
- Vishwadeep Shelke
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani, India
| | - Ajinath Kale
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani, India
| | - Himanshu Sankrityayan
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani, India
| | - Hans-Joachim Anders
- Division of Nephrology, Department of Internal Medicine IV, University Hospital of the Ludwig Maximilians University Munich, Munich, Germany
| | - Anil Bhanudas Gaikwad
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani, India
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14
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Yang N, Zhang Y, Ren P, Zhao L, Zheng D, Fu L, Jin J. LncRNA AA465934 Improves Podocyte Injury by Promoting Tristetraprolin-Mediated HMGB1 DownRegulation in Diabetic Nephropathy. Mol Cell Biol 2024; 44:87-102. [PMID: 38520226 PMCID: PMC10986766 DOI: 10.1080/10985549.2024.2325527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 02/23/2024] [Accepted: 02/26/2024] [Indexed: 03/25/2024] Open
Abstract
Although LncRNA AA465934 expression is reduced in high glucose (HG)-treated podocytes, its role in HG-mediated podocyte injury and diabetic nephropathy (DN) remains unknown. Herein, we investigated the role of AA465934 in HG-mediated podocyte injury and DN using a spontaneous type II diabetic nephropathy (T2DN) model. The model was created by injecting AA465934 overexpressed adeno-associated virus (AAV) or control into mice. The levels of renal function, proteinuria, renal structural lesions, and podocyte apoptosis were then examined. Furthermore, AA465934 and autophagy levels, as well as tristetraprolin (TTP) and high mobility group box 1 (HMGB1) expression changes were detected. We also observed podocyte injury and the binding ability of TTP to E3 ligase proviral insertion in murine lymphomas 2 (PIM2), AA465934, or HMGB1. According to the results, AA465934 improved DN progression and podocyte damage in T2DN mice. In addition, AA465934 bound to TTP and inhibited its degradation by blocking TTP-PIM2 binding. Notably, TTP knock-down blocked the ameliorating effects of AA465934 and TTP bound HMGB1 mRNA, reducing its expression. Overexpression of HMGB1 inhibited the ability of AA465934 and TTP to improve podocyte injury. Furthermore, AA465934 bound TTP, inhibiting TTP-PIM2 binding, thereby suppressing TTP degradation, downregulating HMGB1, and reversing autophagy downregulation, ultimately alleviating HG-mediated podocyte injury and DN. Based on these findings, we deduced that the AA465934/TTP/HMGB1/autophagy axis could be a therapeutic avenue for managing podocyte injury and DN.
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Affiliation(s)
- Nan Yang
- Postgraduate Training Base of Jinzhou Medical University (Zhejiang Provincial People’s Hospital), Jinzhou, Liaoning, China
| | - Yue Zhang
- The Medical College of Qingdao University, Qingdao, China
| | - Peiyao Ren
- Department of Nephrology, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
| | - Li Zhao
- Urology & Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Danna Zheng
- Urology & Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Lanjun Fu
- Department of Nephrology, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
| | - Juan Jin
- Department of Nephrology, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
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15
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Yang Z, Zhou J, Su N, Zhang Z, Chen J, Liu P, Ling P. Insights into the defensive roles of lncRNAs during Mycoplasma pneumoniae infection. Front Microbiol 2024; 15:1330660. [PMID: 38585701 PMCID: PMC10995346 DOI: 10.3389/fmicb.2024.1330660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 02/27/2024] [Indexed: 04/09/2024] Open
Abstract
Mycoplasma pneumoniae causes respiratory tract infections, affecting both children and adults, with varying degrees of severity ranging from mild to life-threatening. In recent years, a new class of regulatory RNAs called long non-coding RNAs (lncRNAs) has been discovered to play crucial roles in regulating gene expression in the host. Research on lncRNAs has greatly expanded our understanding of cellular functions involving RNAs, and it has significantly increased the range of functions of lncRNAs. In lung cancer, transcripts associated with lncRNAs have been identified as regulators of airway and lung inflammation in a process involving protein complexes. An excessive immune response and antibacterial immunity are closely linked to the pathogenesis of M. pneumoniae. The relationship between lncRNAs and M. pneumoniae infection largely involves lncRNAs that participate in antibacterial immunity. This comprehensive review aimed to examine the dysregulation of lncRNAs during M. pneumoniae infection, highlighting the latest advancements in our understanding of the biological functions and molecular mechanisms of lncRNAs in the context of M. pneumoniae infection and indicating avenues for investigating lncRNAs-related therapeutic targets.
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Affiliation(s)
- Zhujun Yang
- Department of Critical Care Medicine, The Central Hospital of Shaoyang City and Affiliated Shaoyang Hospital, Hengyang Medical College, University of South China, Shaoyang, China
- Institute of Pathogenic Biology, Basic Medical School, Hengyang Medical School, University of South China, Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Hengyang, China
| | - Junjun Zhou
- Department of Critical Care Medicine, The Central Hospital of Shaoyang City and Affiliated Shaoyang Hospital, Hengyang Medical College, University of South China, Shaoyang, China
- Institute of Pathogenic Biology, Basic Medical School, Hengyang Medical School, University of South China, Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Hengyang, China
| | - Nana Su
- Department of Critical Care Medicine, The Central Hospital of Shaoyang City and Affiliated Shaoyang Hospital, Hengyang Medical College, University of South China, Shaoyang, China
- Institute of Pathogenic Biology, Basic Medical School, Hengyang Medical School, University of South China, Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Hengyang, China
| | - Zifan Zhang
- Department of Critical Care Medicine, The Central Hospital of Shaoyang City and Affiliated Shaoyang Hospital, Hengyang Medical College, University of South China, Shaoyang, China
- Institute of Pathogenic Biology, Basic Medical School, Hengyang Medical School, University of South China, Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Hengyang, China
| | - Jiaxin Chen
- Department of Critical Care Medicine, The Central Hospital of Shaoyang City and Affiliated Shaoyang Hospital, Hengyang Medical College, University of South China, Shaoyang, China
- Institute of Pathogenic Biology, Basic Medical School, Hengyang Medical School, University of South China, Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Hengyang, China
| | - Peng Liu
- Department of Critical Care Medicine, The Central Hospital of Shaoyang City and Affiliated Shaoyang Hospital, Hengyang Medical College, University of South China, Shaoyang, China
- Institute of Pathogenic Biology, Basic Medical School, Hengyang Medical School, University of South China, Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Hengyang, China
| | - Peng Ling
- Department of Critical Care Medicine, The Central Hospital of Shaoyang City and Affiliated Shaoyang Hospital, Hengyang Medical College, University of South China, Shaoyang, China
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Gan T, Wang Q, Song Y, Shao M, Zhao Y, Guo F, Wei F, Fan X, Zhang W, Luo Y, Chen D, Wang S, Qin G. Canagliflozin improves fatty acid oxidation and ferroptosis of renal tubular epithelial cells via FOXA1-CPT1A axis in diabetic kidney disease. Mol Cell Endocrinol 2024; 582:112139. [PMID: 38128823 DOI: 10.1016/j.mce.2023.112139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 12/15/2023] [Accepted: 12/18/2023] [Indexed: 12/23/2023]
Abstract
Impaired fatty acid oxidation (FAO) is a metabolic hallmark of renal tubular epithelial cells (RTECs) under diabetic conditions. Disturbed FAO may promote cellular oxidative stress and insufficient energy production, leading to ferroptosis subsequently. Canagliflozin, an effective anti-hyperglycemic drug, may exert potential reno-protective effects by upregulating FAO and inhibiting ferroptosis in RTECs. However, the mechanisms involved remain unclear. The present study is aimed to characterize the detailed mechanisms underlying the impact of canagliflozin on FAO and ferroptosis. Type 2 diabetic db/db mice were administrated daily by gavage with canagliflozin (20 mg/kg/day, 40 mg/kg/day) or positive control drug pioglitazone (10 mg/kg/day) for 12 weeks. The results showed canagliflozin effectively improved renal function and structure, reduced lipid droplet accumulation, enhanced FAO with increased ATP contents and CPT1A expression, a rate-limiting enzyme of FAO, and relieved ferroptosis in diabetic mice. Moreover, overexpression of FOXA1, a transcription factor related with lipid metabolism, was observed to upregulate the level of CPT1A, and further alleviated ferroptosis in high glucose cultured HK-2 cells. Whereas FOXA1 knockdown had the opposite effect. Mechanistically, chromatin immunoprecipitation assay and dual-luciferase reporter gene assay results demonstrated that FOXA1 transcriptionally promoted the expression of CPT1A through a sis-inducible element located in the promoter region of the protein. In conclusion, these data suggest that canagliflozin improves FAO and attenuates ferroptosis of RTECs via FOXA1-CPT1A axis in diabetic kidney disease.
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Affiliation(s)
- Tian Gan
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Qingzhu Wang
- Department of Nuclear Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yi Song
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Mingwei Shao
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yanyan Zhao
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Feng Guo
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Fangyi Wei
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Xunjie Fan
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Wei Zhang
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yuanyuan Luo
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Duo Chen
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Shanshan Wang
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Guijun Qin
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
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He YX, Wang T, Li WX, Chen YX. Long noncoding RNA protein-disulfide isomerase-associated 3 regulated high glucose-induced podocyte apoptosis in diabetic nephropathy through targeting miR-139-3p. World J Diabetes 2024; 15:260-274. [PMID: 38464366 PMCID: PMC10921158 DOI: 10.4239/wjd.v15.i2.260] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 12/13/2023] [Accepted: 01/15/2024] [Indexed: 02/04/2024] Open
Abstract
BACKGROUND Podocyte apoptosis plays a vital role in proteinuria pathogenesis in diabetic nephropathy (DN). The regulatory relationship between long noncoding RNAs (lncRNAs) and podocyte apoptosis has recently become another research hot spot in the DN field. AIM To investigate whether lncRNA protein-disulfide isomerase-associated 3 (Pdia3) could regulate podocyte apoptosis through miR-139-3p and revealed the underlying mechanism. METHODS Using normal glucose or high glucose (HG)-cultured podocytes, the cellular functions and exact mechanisms underlying the regulatory effects of lncRNA Pdia3 on podocyte apoptosis and endoplasmic reticulum stress (ERS) were explored. LncRNA Pdia3 and miR-139-3p expression were measured through quantitative real-time polymerase chain reaction. Relative cell viability was detected through the cell counting kit-8 colorimetric assay. The podocyte apoptosis rate in each group was measured through flow cytometry. The interaction between lncRNA Pdia3 and miR-139-3p was examined through the dual luciferase reporter assay. Finally, western blotting was performed to detect the effect of lncRNA Pdia3 on podocyte apoptosis and ERS via miR-139-3p. RESULTS The expression of lncRNA Pdia3 was significantly downregulated in HG-cultured podocytes. Next, lncRNA Pdia3 was involved in HG-induced podocyte apoptosis. Furthermore, the dual luciferase reporter assay confirmed the direct interaction between lncRNA Pdia3 and miR-139-3p. LncRNA Pdia3 overexpression attenuated podocyte apoptosis and ERS through miR-139-3p in HG-cultured podocytes. CONCLUSION Taken together, this study demonstrated that lncRNA Pdia3 overexpression could attenuate HG-induced podocyte apoptosis and ERS by acting as a competing endogenous RNA of miR-139-3p, which might provide a potential therapeutic target for DN.
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Affiliation(s)
- Yin-Xi He
- Department of Orthopaedic Trauma, The Third Hospital of Shijiazhuang, Shijiazhuang 050000, Hebei Province, China
| | - Ting Wang
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Wen-Xian Li
- Department of Endocrinology, The First Hospital of Zhangjiakou, Zhangjiakou 075000, Hebei Province, China
| | - Yan-Xia Chen
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
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Geng M, Liu W, Li J, Yang G, Tian Y, Jiang X, Xin Y. LncRNA as a regulator in the development of diabetic complications. Front Endocrinol (Lausanne) 2024; 15:1324393. [PMID: 38390204 PMCID: PMC10881719 DOI: 10.3389/fendo.2024.1324393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 01/16/2024] [Indexed: 02/24/2024] Open
Abstract
Diabetes is a metabolic disease characterized by hyperglycemia, which induces the production of AGEs, ROS, inflammatory cytokines, and growth factors, leading to the formation of vascular dysfunction and target organ damage, promoting the development of diabetic complications. Diabetic nephropathy, retinopathy, and cardiomyopathy are common complications of diabetes, which are major contributors to disability and death in people with diabetes. Long non-coding RNAs affect gene transcription, mRNA stability, and translation efficiency to influence gene expression for a variety of biological functions. Over the past decade, it has been demonstrated that dysregulated long non-coding RNAs are extensively engaged in the pathogenesis of many diseases, including diabetic complications. Thus, this review discusses the regulations of long non-coding RNAs on the primary pathogenesis of diabetic complications (oxidative stress, inflammation, fibrosis, and microvascular dysfunction), and some of these long non-coding RNAs may function as potential biomarkers or therapeutic targets for diabetic complications.
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Affiliation(s)
- Mengrou Geng
- Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University and College of Basic Medical Science, Jilin University, Changchun, China
- Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Science, Jilin University, Changchun, China
| | - Wei Liu
- Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Science, Jilin University, Changchun, China
| | - Jinjie Li
- Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Science, Jilin University, Changchun, China
| | - Ge Yang
- Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Science, Jilin University, Changchun, China
| | - Yuan Tian
- Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Science, Jilin University, Changchun, China
| | - Xin Jiang
- Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University and College of Basic Medical Science, Jilin University, Changchun, China
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, China
- National Health Commission (NHC) Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, China
| | - Ying Xin
- Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Science, Jilin University, Changchun, China
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王 一, 郭 建, 邵 宝, 陈 海, 蓝 辉. [The Role of TGF-β1/SMAD in Diabetic Nephropathy: Mechanisms and Research Development]. SICHUAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF SICHUAN UNIVERSITY. MEDICAL SCIENCE EDITION 2023; 54:1065-1073. [PMID: 38162063 PMCID: PMC10752761 DOI: 10.12182/20231160108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Indexed: 01/03/2024]
Abstract
Diabetic nephropathy (DN) is a common complication of diabetes and a leading cause of end-stage renal disease. Transforming growth factor-β1 (TGF-β1)/SMAD signaling activation plays an important role in the onset and progression of DN. Reported findings suggest that the activation of TGF-β1 (including the latent form, the active form, and the receptors) and its downstream signaling proteins (SMAD3, SMAD7, etc.) plays a critical role in DN. In addition, TGF-β1/SMAD signaling may mediate the pathogenesis and progression of DN via various microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Emerging evidence shows that TGF-β1, SMAD3, and SMAD7 are the main signaling proteins that contribute to the development of DN, and that they can be potential targets for the treatment of DN. However, recent clinical trials have shown that the anti-TGF-β1 monoclonal antibody treatment fails to effectively alleviate DN, which suggests that upstream inhibition of TGF-β1/SMAD signaling does not alleviate clinical symptoms and that this may be related to the fact that TGF-β1/SMAD has multiple biological effects. Targeted inhibition of the downstream TGF-β1 signaling (e.g., SMAD3 and SMAD7) may be an effective approach to attenuate DN. This article discussed the current understanding of the molecular mechanisms and potential targets for the treatment and prevention of DN by focusing on TGF-β1/SMAD signaling.
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Affiliation(s)
- 一帆 王
- 香港大学中医药学院 （香港 999000）School of Chinese Medicine, The University of Hong Kong, Hong Kong 999000, China
| | - 建波 郭
- 香港大学中医药学院 （香港 999000）School of Chinese Medicine, The University of Hong Kong, Hong Kong 999000, China
| | - 宝仪 邵
- 香港大学中医药学院 （香港 999000）School of Chinese Medicine, The University of Hong Kong, Hong Kong 999000, China
| | - 海勇 陈
- 香港大学中医药学院 （香港 999000）School of Chinese Medicine, The University of Hong Kong, Hong Kong 999000, China
- 香港大学深圳医院 中医部 （深圳 518053）Department of Chinese Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China
| | - 辉耀 蓝
- 香港大学中医药学院 （香港 999000）School of Chinese Medicine, The University of Hong Kong, Hong Kong 999000, China
- 香港大学深圳医院 中医部 （深圳 518053）Department of Chinese Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China
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20
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Bin Wang, Yuan C, Qie Y, Dang S. Long non-coding RNAs and pancreatic cancer: A multifaceted view. Biomed Pharmacother 2023; 167:115601. [PMID: 37774671 DOI: 10.1016/j.biopha.2023.115601] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 09/17/2023] [Accepted: 09/25/2023] [Indexed: 10/01/2023] Open
Abstract
Pancreatic cancer (PC) is a highly malignant disease with a 5-year survival rate of only 10%. Families with PC are at greater risk, as are type 2 diabetes, pancreatitis, and other factors. Insufficient early detection methods make this cancer have a poor prognosis. Additionally, the molecular mechanisms underlying PC development remain unclear. Increasing evidence suggests that long non-coding RNAs (lncRNAs) contribute to PC pathology,which may control gene expression by recruiting histone modification complexes to chromatin and interacting with proteins and RNAs. In recent studies, abnormal regulation of lncRNAs has been implicated in PC proliferation, metastasis, invasion, angiogenesis, apoptosis, and chemotherapy resistance suggesting potential clinical implications. The paper reviews the progress of lncRNA research in PC about diabetes mellitus, pancreatitis, cancer metastasis, tumor microenvironment regulation, and chemoresistance. Furthermore, lncRNAs may serve as potential therapeutic targets and biomarkers for PC diagnosis and prognosis. This will help improve PC patients' survival rate from a lncRNA perspective.
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Affiliation(s)
- Bin Wang
- General Surgery Department, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu 212000, China
| | - Chang Yuan
- General Surgery Department, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu 212000, China
| | - Yinyin Qie
- General Surgery Department, Yixing People's Hospital, Wuxi, Jiangsu 214200, China
| | - Shengchun Dang
- General Surgery Department, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu 212000, China; Siyang Hospital, Suqian, Jiangsu 223700, China.
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21
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Zhao Z, Yan Q, Fang L, Li G, Liu Y, Li J, Pan S, Zhou S, Duan J, Liu D, Liu Z. Identification of urinary extracellular vesicles differentially expressed RNAs in diabetic nephropathy via whole-transcriptome integrated analysis. Comput Biol Med 2023; 166:107480. [PMID: 37738894 DOI: 10.1016/j.compbiomed.2023.107480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 08/30/2023] [Accepted: 09/15/2023] [Indexed: 09/24/2023]
Abstract
BACKGROUND Diabetic nephropathy (DN) is a common systemic microvascular complication of diabetes and a leading cause of chronic kidney disease worldwide. Urinary extracellular vesicles (uEVs), which are natural nanoscale vesicles that protect RNA from degradation, have the potential to serve as an invasive diagnostic biomarker for DN. METHODS We enrolled 24 participants, including twelve with renal biopsy-proven T2DN and twelve with T2DM, and isolated uEVs using ultracentrifugation. We performed microarrays for mRNAs, lncRNAs, and circRNAs in parallel, and Next-Generation Sequencing for miRNAs. Differentially expressed RNAs (DE-RNAs) were subjected to CIBERSORTx, ssGSEA analysis, GO enrichment, PPI network analysis, and construction of the lncRNA/circRNA-miRNA-mRNA regulatory network. Candidate genes and potential biomarker RNAs were validated using databases and machine learning models. RESULTS A total of 1684 mRNAs, 126 lncRNAs, 123 circRNAs and 66 miRNAs were found in uEVs in T2DN samples compared with T2DM. CIBERSORTx revealed the involvement of uEVs in immune activity and ssGSEA explored possible cell or tissue sources of uEVs. A ceRNA co-expression and regulation relationship network was constructed. Candidate genes MYO1C and SP100 mRNA were confirmed to be expressed in the kidney using Nephroseq database, scRNA-seq dataset, and Human Protein Atlas database. We further selected 2 circRNAs, 2 miRNAs, and 2 lncRNAs from WGCNAs and ceRNAs and demonstrated their efficacy as potential diagnostic biomarkers for T2DN using machine learning algorithms. CONCLUSIONS This study reported, for the first time, the whole-transcriptome genetic resources found in urine extracellular vesicles of T2DN patients. The results provide additional support for the possible interactions, and regulators between RNAs from uEVs themselves and as potential biomarkers in DN.
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Affiliation(s)
- Zihao Zhao
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China; Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, PR China; Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, PR China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, PR China; Academy of Medical Science, Zhengzhou University, Zhengzhou, 450052, PR China
| | - Qianqian Yan
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China; Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, PR China; Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, PR China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, PR China; Academy of Medical Science, Zhengzhou University, Zhengzhou, 450052, PR China
| | - Li Fang
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China; Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, PR China; Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, PR China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, PR China; Academy of Medical Science, Zhengzhou University, Zhengzhou, 450052, PR China
| | - Guangpu Li
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China; Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, PR China; Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, PR China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, PR China; Academy of Medical Science, Zhengzhou University, Zhengzhou, 450052, PR China
| | - Yong Liu
- Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, PR China; Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, PR China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, PR China
| | - Jia Li
- Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, PR China; Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, PR China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, PR China
| | - Shaokang Pan
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China; Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, PR China; Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, PR China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, PR China
| | - Sijie Zhou
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China; Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, PR China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, PR China
| | - Jiayu Duan
- Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, PR China; Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, PR China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, PR China
| | - Dongwei Liu
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China; Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, PR China; Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, PR China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, PR China.
| | - Zhangsuo Liu
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China; Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, PR China; Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, PR China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, PR China.
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Wu Q, Huang F. LncRNA H19: a novel player in the regulation of diabetic kidney disease. Front Endocrinol (Lausanne) 2023; 14:1238981. [PMID: 37964955 PMCID: PMC10641825 DOI: 10.3389/fendo.2023.1238981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 10/16/2023] [Indexed: 11/16/2023] Open
Abstract
Diabetic kidney disease (DKD), one of the most severe complications of diabetes mellitus (DM), has received considerable attention owing to its increasing prevalence and contribution to chronic kidney disease (CKD) and end-stage kidney disease (ESRD). However, the use of drugs targeting DKD remains limited. Recent data suggest that long non-coding RNAs (lncRNAs) play a vital role in the development of DKD. The lncRNA H19 is the first imprinted gene, which is expressed in the embryo and down-regulated at birth, and its role in tumors has long been a subject of controversy, however, in recent years, it has received increasing attention in kidney disease. The LncRNA H19 is engaged in the pathological progression of DKD, including glomerulosclerosis and tubulointerstitial fibrosis via the induction of inflammatory responses, apoptosis, ferroptosis, pyroptosis, autophagy, and oxidative damage. In this review, we highlight the most recent research on the molecular mechanism and regulatory forms of lncRNA H19 in DKD, including epigenetic, post-transcriptional, and post-translational regulation, providing a new predictive marker and therapeutic target for the management of DKD.
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Affiliation(s)
| | - Fengjuan Huang
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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23
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Barth J, Loeffler I, Bondeva T, Liebisch M, Wolf G. The Role of Hypoxia on the Trimethylation of H3K27 in Podocytes. Biomedicines 2023; 11:2475. [PMID: 37760919 PMCID: PMC10525388 DOI: 10.3390/biomedicines11092475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 08/28/2023] [Accepted: 09/04/2023] [Indexed: 09/29/2023] Open
Abstract
Epigenetic alterations contribute to the pathogenesis of chronic diseases such as diabetes mellitus. Previous studies of our group showed that diabetic conditions reduce the trimethylation of H3K27 in podocytes in a NIPP1- (nuclear inhibitor of protein phosphatase 1) and EZH2- (enhancer of zeste homolog 2) dependent manner. It has been previously reported that in differentiated podocytes, hypoxia decreases the expression of slit diaphragm proteins and promotes foot process effacement, thereby contributing to the progression of renal disease. The exact mechanisms are, however, not completely understood. The aim of this study was to analyze the role of hypoxia and HIFs (hypoxia-inducible factor) on epigenetic changes in podocytes affecting NIPP1, EZH2 and H3K27me3, in vitro and in vivo. In vivo studies were performed with mice exposed to 10% systemic hypoxia for 3 days or injected with 3,4-DHB (dihydroxybenzoate), a PHD (prolyl hydroxylase) inhibitor, 24 h prior analyses. Immunodetection of H3K27me3, NIPP1 and EZH2 in glomerular podocytes revealed, to the best of our knowledge for the first time, that hypoxic conditions and pharmacological HIFs activation significantly reduce the expression of NIPP1 and EZH2 and diminish H3K27 trimethylation. These findings are also supported by in vitro studies using murine-differentiated podocytes.
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24
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Dieter C, Lemos NE, Girardi E, Ramos DT, Pellenz FM, Canani LH, Assmann TS, Crispim D. The rs3931283/PVT1 and rs7158663/MEG3 polymorphisms are associated with diabetic kidney disease and markers of renal function in patients with type 2 diabetes mellitus. Mol Biol Rep 2023; 50:2159-2169. [PMID: 36565414 DOI: 10.1007/s11033-022-08122-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 11/14/2022] [Indexed: 12/25/2022]
Abstract
BACKGROUND Long non-coding RNAs (lncRNAs) are key regulators of gene expression. Some studies have reported the association of polymorphisms in lncRNA genes with diabetes mellitus (DM) and its chronic complications, including diabetic kidney disease (DKD); however, the results are still inconclusive. Thus, we investigated the association of the rs3200401/MALAT1, rs1894720/MIAT, rs3931283/PVT1, rs11993333/PVT1, rs5749201/TUG1, and rs7158663/MEG3 polymorphisms with DKD in patients with type 2 DM (T2DM). METHODS AND RESULTS This study comprised 902 patients with T2DM and DKD (cases) and 394 patients with T2DM without DKD (controls). The six polymorphisms of interest were genotyped by real-time PCR using TaqMan probes. Frequency of the rs3931283/PVT1 G/G genotype was 36.2% in cases and 31.9% in controls (P = 0.331). After adjustment for gender, glycated hemoglobin, HDL cholesterol, ethnicity, hypertension, and diabetic retinopathy, the G/G genotype was associated with risk for DKD (OR = 1.625, 95% CI 1.020-2.588; P = 0.041). The rs3931283/PVT1 G/G genotype was also associated with higher urinary albumin excretion levels compared to A allele carriers (P = 0.017). No difference was found in rs7158663/MEG3 genotype frequencies between T2DM controls and DKD patients (OR = 1.087, 95% CI 0.686-1.724; P = 0.722). However, the rs7158663/MEG3 G/G genotype was associated with protection against severe DKD (OR = 0.694, 95% CI 0.488-0.989; P = 0.043, for patients with severe DKD vs. T2DM controls). The rs7158663/MEG3 G/G genotype was also associated with lower creatinine levels (P = 0.007) and higher estimated glomerular filtration rate (P = 0.010) compared to A allele carriers. No association was found between the rs11993333/PVT1, rs3200401/MALAT1, rs1894720/MIAT, and rs5749201/TUG1 polymorphisms and DKD or its laboratory markers. CONCLUSION The rs3931283/PVT1 G/G and rs7158663/MEG3 G/G are associated with DKD and markers of renal function in T2DM patients from a Brazilian population.
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Affiliation(s)
- Cristine Dieter
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350; prédio 12; 4° andar, 90035-003, Porto Alegre, Rio Grande do Sul, Brazil.,Graduate Program in Medical Sciences: Endocrinology, Faculty of Medicine, Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Natália Emerim Lemos
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350; prédio 12; 4° andar, 90035-003, Porto Alegre, Rio Grande do Sul, Brazil.,Department of Biochemistry, Institute of Chemistry, Universidade de São Paulo, São Paulo, Brazil
| | - Eliandra Girardi
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350; prédio 12; 4° andar, 90035-003, Porto Alegre, Rio Grande do Sul, Brazil
| | - Denise Taurino Ramos
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350; prédio 12; 4° andar, 90035-003, Porto Alegre, Rio Grande do Sul, Brazil
| | - Felipe Mateus Pellenz
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350; prédio 12; 4° andar, 90035-003, Porto Alegre, Rio Grande do Sul, Brazil.,Graduate Program in Medical Sciences: Endocrinology, Faculty of Medicine, Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Luís Henrique Canani
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350; prédio 12; 4° andar, 90035-003, Porto Alegre, Rio Grande do Sul, Brazil.,Graduate Program in Medical Sciences: Endocrinology, Faculty of Medicine, Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Taís Silveira Assmann
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350; prédio 12; 4° andar, 90035-003, Porto Alegre, Rio Grande do Sul, Brazil.,Graduate Program in Medical Sciences: Endocrinology, Faculty of Medicine, Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Daisy Crispim
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350; prédio 12; 4° andar, 90035-003, Porto Alegre, Rio Grande do Sul, Brazil. .,Graduate Program in Medical Sciences: Endocrinology, Faculty of Medicine, Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
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25
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Zhao Y, Li D, Zhou P, Zhao Y, Kuang J. microRNA-29b-3p attenuates diabetic nephropathy in mice by modifying EZH2. Hormones (Athens) 2023; 22:223-233. [PMID: 36692688 DOI: 10.1007/s42000-022-00426-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 11/30/2022] [Indexed: 01/25/2023]
Abstract
OBJECTIVE Diabetic nephropathy (DN) is the leading cause of end-stage renal disease around the world. This study investigated the role of microRNA (miR)-29b-3p in DN and the mechanism of the miR-29b-3p/EZH2 axis in DN. METHODS Peripheral blood samples of DN patients were collected and miR-29b-3p and EZH2 expression levels were evaluated using RT-qPCR. DN mouse models were successfully established, and then treated with miR-29b-3p overexpression or EZH2 silence. IL-1β, IL-6, and TNF-α levels were assessed by ELISA. Blood glucose, serum creatinine (Scr), 24-h urine volume, 24-h urine protein, and blood urea nitrogen (BUN) levels were examined by automatic biochemical analyzer detection. HE staining was performed to observe the renal histopathology, and TUNEL staining was implemented to test apoptosis in renal tissues. The binding relationship between miR-29b-3p and EZH2 was validated by using a bioinformatics website and dual luciferase reporter gene assay. RESULTS miR-29b-3p was lowly expressed, and EZH2 was highly expressed in patients with DN. Overexpressing miR-29b-3p or silencing EZH2 attenuated renal dysfunction, suppressed inflammation and apoptosis, and relieved renal injuries in mice with DN. miR-29b-3p inhibited EZH2, and miR-29b-3p overexpression mitigated renal injuries in DN mice by repressing EZH2. CONCLUSION miR-29b-3p suppresses EZH2 expression thereby inhibiting the progression of DN in mice.
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Affiliation(s)
- Yurong Zhao
- Department of Endocrinology, the Fourth People's Hospital of Shenyang, Shenyang, 110000, Liaoning, China
| | - Dandan Li
- Department of Endocrinology, the Fourth People's Hospital of Shenyang, Shenyang, 110000, Liaoning, China
| | - Ping Zhou
- Department of Anesthesiology, Suizhou Maternal and Child Health Hospital, Suizhou, 441300, Hubei, China
| | - Yujie Zhao
- Shenzhen Yuce Biological Technology Company, Shenzhen, 518172, Guangdong, China
| | - Jinsong Kuang
- Department of Endocrinology, the Fourth People's Hospital of Shenyang, Shenyang, 110000, Liaoning, China.
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Wang X, Zhao J, Li Y, Rao J, Xu G. Epigenetics and endoplasmic reticulum in podocytopathy during diabetic nephropathy progression. Front Immunol 2022; 13:1090989. [PMID: 36618403 PMCID: PMC9813850 DOI: 10.3389/fimmu.2022.1090989] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 11/30/2022] [Indexed: 12/24/2022] Open
Abstract
Proteinuria or nephrotic syndrome are symptoms of podocytopathies, kidney diseases caused by direct or indirect podocyte damage. Human health worldwide is threatened by diabetic nephropathy (DN), the leading cause of end-stage renal disease (ESRD) in the world. DN development and progression are largely dependent on inflammation. The effects of podocyte damage on metabolic disease and inflammatory disorders have been documented. Epigenetic and endoplasmic reticulum (ER) stress are also evident in DN. Targeting inflammation pathway and ER stress in podocytes may be a prospective therapy to prevent the progression of DN. Here, we review the mechanism of epigenetics and ER stress on podocyte inflammation and apoptosis, and discuss the potential amelioration of podocytopathies by regulating epigenetics and ER stress as well as by targeting inflammatory signaling, which provides a theoretical basis for drug development to ameliorate DN.
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Affiliation(s)
- Xiaokang Wang
- Department of Pharmacy, Shenzhen Longhua District Central Hospital, The Affiliated Central Hospital of Shenzhen Longhua District, Guangdong Medical University, Shenzhen, China,*Correspondence: Xiaokang Wang,
| | - Jingqian Zhao
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Yuanqing Li
- Department of Pharmacy, Shenzhen Longhua District Central Hospital, The Affiliated Central Hospital of Shenzhen Longhua District, Guangdong Medical University, Shenzhen, China
| | - Jiaoyu Rao
- Department of Pharmacy, Shenzhen Longhua District Central Hospital, The Affiliated Central Hospital of Shenzhen Longhua District, Guangdong Medical University, Shenzhen, China
| | - Gengrui Xu
- Department of Pharmacy, Shenzhen Longhua District Central Hospital, The Affiliated Central Hospital of Shenzhen Longhua District, Guangdong Medical University, Shenzhen, China
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Mok H, Al-Jumaily A, Lu J. Plasmacytoma Variant Translocation 1 (PVT1) Gene as a Potential Novel Target for the Treatment of Diabetic Nephropathy. Biomedicines 2022; 10:2711. [PMID: 36359234 PMCID: PMC9687488 DOI: 10.3390/biomedicines10112711] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/08/2022] [Accepted: 10/21/2022] [Indexed: 01/29/2024] Open
Abstract
Introduction: Diabetic nephropathy (DN), a severe microvascular complication in patients with diabetes, is clinically characterized by progressive decline in glomerular filtration rate (GFR). DN is the most common cause of end-stage renal disease (ESRD), and has a consistently high mortality rate. Despite the fact that the prevalence of DN is increasing worldwide, the molecular mechanism underlying the pathogenesis of DN is not fully understood. Previous studies indicated PVT1 as a key determinant of ESRD as well as a mediator of extracellular matrix (ECM) accumulation in vitro. More investigations into the role of PVT1 in DN development are needed. Objectives: To study the effect of PVT1 silencing on progression of DN in diabetic male C57BL/6 mice at early, intermediate and relatively advanced ages. Methods: Diabetic mice were treated with either scramble-siRNA (DM + siRNA (scramble)) or PVT1-siRNA (DM + siRNA (PVT1)), whereas the control mice were normal mice without siRNA injection (Control). Blood, urine and kidney were collected at the age of 9 (young), 16 (middle-aged) or 24 (old) weeks old. Kidney function, histology and molecular gene expression were evaluated. Results: Our findings showed that silencing of PVT1 reduced kidney hypertrophy, proteinuria (UAE, UACR, UPE, UPCR), serum creatinine, serum TGF-β1, serum insulin decline, glomerular and mesangial areas, and increased creatinine clearance in diabetic mice to levels closer to the age-matched controls. Also, silencing of PVT1 markedly suppressed the upregulation of PAI-1, TGF-β1, FN1, COL4A1, and downregulation of BMP7. Conclusion: Silencing of PVT1 ameliorates DN in terms of kidney function and histology in diabetic mice. The renoprotection is attributed to the reduction in ECM accumulation, TGF-β1 elevation and insulin decline. PVT1 is suggested to play an important role in ECM accumulation which makes it a possible target for the treatment of DN.
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Affiliation(s)
- Helen Mok
- School of Science, Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland 1142, New Zealand
| | - Ahmed Al-Jumaily
- School of Engineering, Computer and Mathematical Sciences, Faculty of Design and Creative Technologies, Auckland University of Technology, Auckland 1142, New Zealand
| | - Jun Lu
- School of Science, Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland 1142, New Zealand
- Maurice Wilkins Centre for Molecular Discovery, Auckland 1142, New Zealand
- College of Food Science and Technology, Nanchang University, Nanchang 330031, China
- College of Food Engineering and Nutrition Sciences, Shaanxi Normal University, Xi’an 710119, China
- School of Perfume and Aroma Technology, Shanghai Institute of Technology, Shanghai 201418, China
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28
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Wang S, Zhang X, Wang Q, Wang R. Histone modification in podocyte injury of diabetic nephropathy. J Mol Med (Berl) 2022; 100:1373-1386. [PMID: 36040515 DOI: 10.1007/s00109-022-02247-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 07/31/2022] [Accepted: 08/17/2022] [Indexed: 11/24/2022]
Abstract
Diabetic nephropathy (DN), an important complication of diabetic microvascular disease, is one of the leading causes of end-stage renal disease (ESRD), which brings heavy burdens to the whole society. Podocytes are terminally differentiated glomerular cells, which act as a pivotal component of glomerular filtration barrier. When podocytes are injured, glomerular filtration barrier is damaged, and proteinuria would occur. Dysfunction of podocytes contributes to DN. And degrees of podocyte injury influence prognosis of DN. Growing evidences have shown that epigenetics does a lot in the evolvement of podocyte injury. Epigenetics includes DNA methylation, histone modification, and non-coding RNA. Among them, histone modification plays an indelible role. Histone modification includes histone methylation, histone acetylation, and other modifications such as histone phosphorylation, histone ubiquitination, histone ADP-ribosylation, histone crotonylation, and histone β-hydroxybutyrylation. It can affect chromatin structure and regulate gene transcription to exert its function. This review is to summarize documents about pathogenesis of podocyte injury, most importantly, histone modification of podocyte injury in DN recently to provide new ideas for further molecular research, diagnosis, and treatment.
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Affiliation(s)
- Simeng Wang
- Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, 250012, Shandong, China
| | - Xinyu Zhang
- Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, 250012, Shandong, China
| | - Qinglian Wang
- Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, 250012, Shandong, China. .,Department of Nephrology, Shandong Provincial Hospital, Shandong First Medical University, No. 324 Jingwu Street, Jinan, 250021, Shandong, China.
| | - Rong Wang
- Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, 250012, Shandong, China. .,Department of Nephrology, Shandong Provincial Hospital, Shandong First Medical University, No. 324 Jingwu Street, Jinan, 250021, Shandong, China.
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29
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Nadhan R, Isidoro C, Song YS, Dhanasekaran DN. Signaling by LncRNAs: Structure, Cellular Homeostasis, and Disease Pathology. Cells 2022; 11:2517. [PMID: 36010595 PMCID: PMC9406440 DOI: 10.3390/cells11162517] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/09/2022] [Accepted: 08/11/2022] [Indexed: 12/11/2022] Open
Abstract
The cellular signaling network involves co-ordinated regulation of numerous signaling molecules that aid the maintenance of cellular as well as organismal homeostasis. Aberrant signaling plays a major role in the pathophysiology of many diseases. Recent studies have unraveled the superfamily of long non-coding RNAs (lncRNAs) as critical signaling nodes in diverse signaling networks. Defective signaling by lncRNAs is emerging as a causative factor underlying the pathophysiology of many diseases. LncRNAs have been shown to be involved in the multiplexed regulation of diverse pathways through both genetic and epigenetic mechanisms. They can serve as decoys, guides, scaffolds, and effector molecules to regulate cell signaling. In comparison with the other classes of RNAs, lncRNAs possess unique structural modifications that contribute to their diversity in modes of action within the nucleus and cytoplasm. In this review, we summarize the structure and function of lncRNAs as well as their vivid mechanisms of action. Further, we provide insights into the role of lncRNAs in the pathogenesis of four major disease paradigms, namely cardiovascular diseases, neurological disorders, cancers, and the metabolic disease, diabetes mellitus. This review serves as a succinct treatise that could open windows to investigate the role of lncRNAs as novel therapeutic targets.
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Affiliation(s)
- Revathy Nadhan
- Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Ciro Isidoro
- Laboratory of Molecular Pathology and NanoBioImaging, Department of Health Sciences, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Yong Sang Song
- Department of Obstetrics and Gynecology, Cancer Research Institute, College of Medicine, Seoul National University, Seoul 151-921, Korea
| | - Danny N. Dhanasekaran
- Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Department of Cell Biology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
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Zhang X, Ren L, Wei J, Ni Y, Sun L, Zhao X, Zhang Y, Qiao H. Silencing long noncoding RNA-CES1P1 suppresses glomerular endothelial cell inflammation in diabetic nephropathy. Int Immunopharmacol 2022; 110:108820. [PMID: 35834955 DOI: 10.1016/j.intimp.2022.108820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 04/23/2022] [Accepted: 04/28/2022] [Indexed: 11/26/2022]
Abstract
Diabetic nephropathy (DN) has become the main cause of end-stage renal disease worldwide. Inflammation is associated with the occurrence and development of DN, and long noncoding RNAs (lncRNAs) are involved in the regulation of inflammatory processes. This study aims to determine the role and mechanism of lncRNA-CES1P1 in DN.C57BL/6 mice and human umbilical vein endothelial cells (HUVECs) were used for this experimental study. In vivo experimental intraperitoneal injection of streptozotocin (STZ) to construct a diabetes mellitus (DM) model in C57BL/6 mice caused increased expression of lncRNA-CES1P1, decreased expression of miR-214-3p in kidney tissue, and produced renal inflammation and proteinuria. Exogenous knockdown of lncRNA-CES1P1 expression decreased renal inflammatory infiltration. In vitro experiments using high glucose (HG) stimulation of HUVECs cell revealed increased expression of lncRNA-CES1P1, decreased expression of miR-214-3p, and increased expression of the inflammatory factors IL-17, IκB, NF-κB, and IL-6. Luciferase reporter assays showed direct targets of miR-214-3p interaction with lncRNA-CES1P1 and IL-17. These results suggest that hyperglycemia represses miR-214-3p by inducing lncRNA-CES1P1, which promotes the expression of the inflammatory factors IL-17, IκB, NF-κB and IL-6 ultimately leading to the development of DN. Interfering with lncRNA-CES1P1 can reduce hyperglycemia-induced DN.
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Affiliation(s)
- Xiaona Zhang
- Department of Endocrinology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
| | - Long Ren
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, China.
| | - Jiaxing Wei
- Department of Endocrinology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
| | - Yanan Ni
- Department of Endocrinology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
| | - Lulu Sun
- Department of Endocrinology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
| | - Xiaoyu Zhao
- Department of Endocrinology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
| | - Yaguang Zhang
- Department of Endocrinology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
| | - Hong Qiao
- Department of Endocrinology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
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31
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Wu F, Zhu Y, Zhou C, Gui W, Li H, Lin X. Regulation mechanism and pathogenic role of lncRNA plasmacytoma variant translocation 1 (PVT1) in human diseases. Genes Dis 2022. [DOI: 10.1016/j.gendis.2022.05.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022] Open
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Sun M, Yan S, Zhao D, Wang L, Feng T, Yang Y, Li X, Hu W, Yao N, Cui W, Li B. Identified lncRNAs functional modules and genes in prediabetes with hypertriglyceridemia by weighted gene co-expression network analysis. Nutr Metab (Lond) 2022; 19:33. [PMID: 35501901 PMCID: PMC9063339 DOI: 10.1186/s12986-022-00665-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 03/08/2022] [Indexed: 11/21/2022] Open
Abstract
Background Hypertriglyceridemia (HTG) is one of the most important comorbidities in abnormal glucose patients. The aim of this study was to identify lncRNAs functional modules and hub genes related to triglyceride (TG) in prediabetes. Methods The study included 12 prediabetic patients: 6 participants with HTG and 6 participants with normal triglyceride (NTG). Whole peripheral blood RNA sequencing was performed for these samples to establish a lncRNA library. WGCNA, KEGG pathways analysis and the PPI network were used to construct co‐expression network, to obtain modules related to blood glucose, and to detect key lncRNAs. Meanwhile, GEO database and qRT-PCR were used to validate above key lncRNAs. Results We found out that the TCONS_00334653 and PVT1, whose target mRNA are MYC and HIST1H2BM, were downregulating in the prediabetes with HTG. Moreover, both of TCONS_00334653 and PVT1 were validated in the GEO database and qRT-PCR. Conclusions Therefore, the TCONS_00334653 and PVT1 were detected the key lncRNAs for the prediabetes with HTG, which might be a potential therapeutic or diagnostic target for the treatment of prediabetes with HTG according to the results of validation in the GEO database, qRT-PCR and ROC curves. Supplementary Information The online version contains supplementary material available at 10.1186/s12986-022-00665-5.
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Affiliation(s)
- Mengzi Sun
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, 1163 Xinmin Avenue, Changchun, 130021, People's Republic of China
| | - Shoumeng Yan
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, 1163 Xinmin Avenue, Changchun, 130021, People's Republic of China
| | - Di Zhao
- Department of Physical Examination Central, The First Hospital of Jilin University, Changchun, 130021, People's Republic of China
| | - Ling Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, 1163 Xinmin Avenue, Changchun, 130021, People's Republic of China
| | - Tianyu Feng
- Department of Social Medicine and Health Management, School of Public Health, Jilin University, Changchun, 130021, People's Republic of China
| | - Yixue Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, 1163 Xinmin Avenue, Changchun, 130021, People's Republic of China
| | - Xiaotong Li
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, 1163 Xinmin Avenue, Changchun, 130021, People's Republic of China
| | - Wenyu Hu
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, 1163 Xinmin Avenue, Changchun, 130021, People's Republic of China
| | - Nan Yao
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, 1163 Xinmin Avenue, Changchun, 130021, People's Republic of China
| | - Weiwei Cui
- Department of Nutrition and Food Hygiene, School of Public Health, Jilin University, 1163 Xinmin Avenue, Changchun, 130021, People's Republic of China.
| | - Bo Li
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, 1163 Xinmin Avenue, Changchun, 130021, People's Republic of China.
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Guo J, Chen Y, Xu J, Li L, Dang W, Xiao F, Ren W, Zhu Y, Du Q, Li Q, Li X. Long noncoding RNA PVT1 regulates the proliferation and apoptosis of ARPE-19 cells in vitro via the miR-1301-3p/KLF7 axis. Cell Cycle 2022; 21:1590-1598. [PMID: 35451342 PMCID: PMC9291708 DOI: 10.1080/15384101.2022.2058839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Diabetic retinopathy (DR) as a frequent diabetic microvascular complication shows signs in one-third of diabetic patients. Long non-coding RNAs (lncRNAs) have drawn increasing attention because of their regulatory roles in DR. LncRNA plasmacytoma variant translocation 1 (PVT1) is documented to be upregulated in diabetes-related diseases, while its effects in DR remains unexplored. ARPE-19 cells under the treatment of high-glucose (HG) were used as DR cell models. The gene expression in ARPE-19 cells was examined using RT-qPCR. The viability and apoptosis of ARPE-19 cells were determined by MTT and TUNEL assays. The levels of inflammation-associated proteins or mRNA were measured using western blot. Luciferase reporter assay and RNA pull down assay were conducted for the exploration of the underlying mechanism of PVT1. PVT1 was revealed to be upregulated in DR cell models. Silencing of PVT1 promoted the viability and inhibited apoptosis of HG-stimulated ARPE-19 cells. The results revealed that PVT1 can bind with miR-1301-3p. PVT1 negatively modulated miR-1301-3p expression. Additionally, KLF7 was targeted by miR-1301-3p. PVT1 upregulated KLF7 expression by binding with miR-1301-3p. The silenced PVT1-mediated influence on cell viability and cell apoptosis was rescued by overexpression of KLF7. PVT1 suppresses proliferation and promotes apoptosis of ARPE-19 cells treated with HG in vitro by binding with miR-1301-3p to upregulate KLF7.
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Affiliation(s)
- Jianjin Guo
- Department of General Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.,Department of General Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yuan Chen
- Department of General Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.,Department of General Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jiajia Xu
- Department of General Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.,Department of General Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Liqi Li
- Department of General Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.,Department of General Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wenjiao Dang
- School of Medicine, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Feng Xiao
- Department of Oncology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Wei Ren
- Department of Endocrinology and Metabolism, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Taiyuan, Shanxi, China
| | - Yikun Zhu
- Department of Endocrinology and Metabolism, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Qiujing Du
- School of Medicine, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Qian Li
- School of Medicine, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xing Li
- Department of Endocrinology and Metabolism, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
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Hu M, Ma Q, Liu B, Wang Q, Zhang T, Huang T, Lv Z. Long Non-Coding RNAs in the Pathogenesis of Diabetic Kidney Disease. Front Cell Dev Biol 2022; 10:845371. [PMID: 35517509 PMCID: PMC9065414 DOI: 10.3389/fcell.2022.845371] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 03/08/2022] [Indexed: 01/09/2023] Open
Abstract
Diabetic kidney disease (DKD) is one of the major microvascular complications of diabetes mellitus, with relatively high morbidity and mortality globally but still in short therapeutic options. Over the decades, a large body of data has demonstrated that oxidative stress, inflammatory responses, and hemodynamic disorders might exert critical influence in the initiation and development of DKD, whereas the delicate pathogenesis of DKD remains profoundly elusive. Recently, long non-coding RNAs (lncRNAs), extensively studied in the field of cancer, are attracting increasing attentions on the development of diabetes mellitus and its complications including DKD, diabetic retinopathy, and diabetic cardiomyopathy. In this review, we chiefly focused on abnormal expression and function of lncRNAs in major resident cells (mesangial cell, endothelial cell, podocyte, and tubular epithelial cell) in the kidney, summarized the critical roles of lncRNAs in the pathogenesis of DKD, and elaborated their potential therapeutic significance, in order to advance our knowledge in this field, which might help in future research and clinical treatment for the disease.
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Affiliation(s)
- Mengsi Hu
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Department of Nephrology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Qiqi Ma
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Bing Liu
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Department of Nephrology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Qianhui Wang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Tingwei Zhang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Tongtong Huang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Zhimei Lv
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Department of Nephrology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- *Correspondence: Zhimei Lv,
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Xu J, Wang Q, Song YF, Xu XH, Zhu H, Chen PD, Ren YP. Long noncoding RNA X-inactive specific transcript regulates NLR family pyrin domain containing 3/caspase-1-mediated pyroptosis in diabetic nephropathy. World J Diabetes 2022; 13:358-375. [PMID: 35582664 PMCID: PMC9052004 DOI: 10.4239/wjd.v13.i4.358] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 01/24/2022] [Accepted: 03/17/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND NLRP3-mediated pyroptosis is recognized as an essential modulator of renal disease pathology. Long noncoding RNAs (lncRNAs) are active participators of diabetic nephropathy (DN). X inactive specific transcript (XIST) expression has been reported to be elevated in the serum of DN patients.
AIM To evaluate the mechanism of lncRNA XIST in renal tubular epithelial cell (RTEC) pyroptosis in DN.
METHODS A DN rat model was established through streptozotocin injection, and XIST was knocked down by tail vein injection of the lentivirus LV sh-XIST. Renal metabolic and biochemical indices were detected, and pathological changes in the renal tissue were assessed. The expression of indicators related to inflammation and pyroptosis was also detected. High glucose (HG) was used to treat HK2 cells, and cell viability and lactate dehydrogenase (LDH) activity were detected after silencing XIST. The subcellular localization and downstream mechanism of XIST were investigated. Finally, a rescue experiment was carried out to verify that XIST regulates NLR family pyrin domain containing 3 (NLRP3)/caspase-1-mediated RTEC pyroptosis through the microRNA-15-5p (miR-15b-5p)/Toll-like receptor 4 (TLR4) axis.
RESULTS XIST was highly expressed in the DN models. XIST silencing improved renal metabolism and biochemical indices and mitigated renal injury. The expression of inflammation and pyroptosis indicators was significantly increased in DN rats and HG-treated HK2 cells; cell viability was decreased and LDH activity was increased after HG treatment. Silencing XIST inhibited RTEC pyroptosis by inhibiting NLRP3/caspase-1. Mechanistically, XIST sponged miR-15b-5p to regulate TLR4. Silencing XIST inhibited TLR4 by promoting miR-15b-5p. miR-15b-5p inhibition or TLR4 overexpression averted the inhibitory effect of silencing XIST on HG-induced RTEC pyroptosis.
CONCLUSION Silencing XIST inhibits TLR4 by upregulating miR-15b-5p and ultimately inhibits renal injury in DN by inhibiting NLRP3/caspase-1-mediated RTEC pyroptosis.
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Affiliation(s)
- Jia Xu
- Department of Nephrology, Shenzhen University General Hospital, Shenzhen 518000, Guangdong Province, China
| | - Qin Wang
- Department of Nephrology, Shenzhen University General Hospital, Shenzhen 518000, Guangdong Province, China
| | - Yi-Fan Song
- Department of Nephrology, Shenzhen University General Hospital, Shenzhen 518000, Guangdong Province, China
| | - Xiao-Hui Xu
- Department of Nephrology, Shenzhen University General Hospital, Shenzhen 518000, Guangdong Province, China
| | - He Zhu
- Department of Nephrology, Shenzhen University General Hospital, Shenzhen 518000, Guangdong Province, China
| | - Pei-Dan Chen
- Department of Nephrology, Shenzhen University General Hospital, Shenzhen 518000, Guangdong Province, China
| | - Ye-Ping Ren
- Department of Nephrology, Shenzhen University General Hospital, Shenzhen 518000, Guangdong Province, China
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Traversa D, Simonetti G, Tolomeo D, Visci G, Macchia G, Ghetti M, Martinelli G, Kristensen LS, Storlazzi CT. Unravelling similarities and differences in the role of circular and linear PVT1 in cancer and human disease. Br J Cancer 2022; 126:835-850. [PMID: 34754096 PMCID: PMC8927338 DOI: 10.1038/s41416-021-01584-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 08/27/2021] [Accepted: 10/04/2021] [Indexed: 12/15/2022] Open
Abstract
The plasmacytoma variant translocation 1 (PVT1) is a long non-coding RNA gene involved in human disease, mainly in cancer onset/progression. Although widely analysed, its biological roles need to be further clarified. Notably, functional studies on PVT1 are complicated by the occurrence of multiple transcript variants, linear and circular, which generate technical issues in the experimental procedures used to evaluate its impact on human disease. Among the many PVT1 transcripts, the linear PVT1 (lncPVT1) and the circular hsa_circ_0001821 (circPVT1) are frequently reported to perform similar pathologic and pro-tumorigenic functions when overexpressed. The stimulation of cell proliferation, invasion and drug resistance, cell metabolism regulation, and apoptosis inhibition is controlled through multiple targets, including MYC, p21, STAT3, vimentin, cadherins, the PI3K/AKT, HK2, BCL2, and CASP3. However, some of this evidence may originate from an incorrect evaluation of these transcripts as two separate molecules, as they share the lncPVT1 exon-2 sequence. We here summarise lncPVT1/circPVT1 functions by mainly focusing on shared pathways, pointing out the potential bias that may exist when the biological role of each transcript is analysed. These considerations may improve the knowledge about lncPVT1/circPVT1 and their specific targets, which deserve further studies due to their diagnostic, prognostic, and therapeutic potential.
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Affiliation(s)
- Debora Traversa
- Department of Biology, University of Bari "Aldo Moro", Bari, Italy
| | - Giorgia Simonetti
- IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, FC, Italy
| | - Doron Tolomeo
- Department of Biology, University of Bari "Aldo Moro", Bari, Italy
| | - Grazia Visci
- Department of Biology, University of Bari "Aldo Moro", Bari, Italy
| | - Gemma Macchia
- Department of Biology, University of Bari "Aldo Moro", Bari, Italy
| | - Martina Ghetti
- IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, FC, Italy
| | - Giovanni Martinelli
- IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, FC, Italy
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Wang X, Chen W, Lao W, Chen Y. Silencing LncRNA PVT1 Reverses High Glucose-Induced Regulation of the High Expression of PVT1 in HRMECs by Targeting miR-128-3p. Horm Metab Res 2022; 54:119-125. [PMID: 35130573 DOI: 10.1055/a-1730-5091] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
This paper aims to discuss the possibility of lncRNA PVT1 as a diagnostic biomarker for diabetic retinopathy (DR) and explore the underlying mechanism. Real-time quantitative polymerase chain reaction (RT-qPCR) was selected to determine the expression level of lncRNA PVT1 in the serum of all subjects. The receiver operating characteristic (ROC) curve reflected the diagnostic significance of PVT1 for DR patients. The Cell Counting Kit-8 (CCK-8) and Transwell assays were used to evaluate the effect of PVT1 expression on the proliferation and migration of human retinal microvascular endothelial cells (HRMECs). The luciferase reporter gene was selected to verify the interaction between PVT1 and miR-128-3p. The relative expression level of PVT1 in serum was higher in both the DB and DR group than in the healthy controls group (HC), and it was highest in the DR group. ROC curve indicated that serum PVT1 could distinguish between HC and DB patients, DB patients and DR patients, respectively. In vitro, high glucose induction significantly increased the proliferation and migration capabilities of HRMECs, but silencing PVT1 (si-PVT1) downregulated the proliferation and migration capabilities of HRMECs. The detection of luciferase reporter gene showed that lncRNA PVT1 targeted miR-128-3p, and there was a negative correlation in the serum of DR patients. In conclusion, this study confirmed that lncRNA PVT1 might regulate the process of DR by targeting miR-128-3p, and has the potential as a biomarker for the diagnosis of DR.
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Affiliation(s)
- Xuyang Wang
- Hainan Eye Hospital and Key Laboratory of Ophthalmology, Zhongshan Opthalmic Center, Sun Yat-sen University, Haikou, 570311, Hainan Province, China
| | - Wangling Chen
- Hainan Eye Hospital and Key Laboratory of Ophthalmology, Zhongshan Opthalmic Center, Sun Yat-sen University, Haikou, 570311, Hainan Province, China
| | - Wei Lao
- Hainan Eye Hospital and Key Laboratory of Ophthalmology, Zhongshan Opthalmic Center, Sun Yat-sen University, Haikou, 570311, Hainan Province, China
| | - Yunxin Chen
- Hainan Eye Hospital and Key Laboratory of Ophthalmology, Zhongshan Opthalmic Center, Sun Yat-sen University, Haikou, 570311, Hainan Province, China
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Yu Q, Lin J, Ma Q, Li Y, Wang Q, Chen H, Liu Y, Liu B. Long Noncoding RNA ENSG00000254693 Promotes Diabetic Kidney Disease via Interacting with HuR. J Diabetes Res 2022; 2022:8679548. [PMID: 35493610 PMCID: PMC9042635 DOI: 10.1155/2022/8679548] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 03/28/2022] [Accepted: 04/02/2022] [Indexed: 01/14/2023] Open
Abstract
Diabetic kidney disease (DKD) is one of the most common complications of diabetes mellitus (DM), without suitable therapies, causing end-stage renal diseases (ESRDs) ultimately. Moreover, there is increasing evidence demonstrating that long noncoding RNAs (lncRNAs) play crucial roles in the development of DKD. Our RNA sequencing data revealed a large group of differentially expressed lncRNAs in renal tissues of DKD, of which lncRNA ENSG00000254693 (lncRNA 254693 for short) changed drastically. In this study, we found that the expression of lncRNA 254693 was increased in both DKD patients and high-glucose-induced human podocytes. 5'/3'RACE and Northern blot assays were used to find the full length of lncRNA ENSG00000254693 which is 558 nucleotides and nonisoform that existed in human podocyte. Downregulation of lncRNA 254693 remarkably reversed the elevation of inflammation, apoptosis, and podocyte injury caused by high glucose. Then, we did bioinformatics analysis via RBPDB and found that lncRNA 254693 can combine with HuR, a RNA binding protein. Meanwhile, immunofluorescence and in situ hybridization double staining was used to prove the existence of colocalization between them. Intriguingly, lncRNA 254693 knockdown decreased HuR levels, while HuR knockdown also decreased the level of lncRNA 254693 and its stability. After this, RNA immunoprecipitation assay results confirmed the binding association between them again. In addition, we found that HuR was increased in high glucose-induced podocytes, and the silence of HuR could alleviate podocyte injury, inflammation, and apoptosis. These results together suggested a novel feedback regulation between lncRNA 254693 and HuR which could involve in podocyte injury and may serve as a predicted target for DKD therapies.
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Affiliation(s)
- Qun Yu
- Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, 250021 Shandong, China
| | - Jiangong Lin
- Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, 250021 Shandong, China
| | - Qiqi Ma
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021 Shandong, China
| | - Yanmei Li
- Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, 250021 Shandong, China
| | - Qianhui Wang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021 Shandong, China
| | - Huimin Chen
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021 Shandong, China
| | - Yue Liu
- Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, 250021 Shandong, China
| | - Bing Liu
- Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, 250021 Shandong, China
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021 Shandong, China
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Ming J, Sana SRGL, Deng X. Identification of copper-related biomarkers and potential molecule mechanism in diabetic nephropathy. Front Endocrinol (Lausanne) 2022; 13:978601. [PMID: 36329882 PMCID: PMC9623046 DOI: 10.3389/fendo.2022.978601] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Accepted: 10/05/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Diabetic nephropathy (DN) is a chronic microvascular complication in patients with diabetes mellitus, which is the leading cause of end-stage renal disease. However, the role of copper-related genes (CRGs) in DN development remains unclear. MATERIALS AND METHODS CRGs were acquired from the GeneCards and NCBI databases. Based on the GSE96804 and GSE111154 datasets from the GEO repository, we identified hub CRGs for DN progression by taking the intersection of differentially expressed CRGs (DECRGs) and genes in the key module from Weighted Gene Co-expression Network Analysis. The Maximal Clique Centrality algorithm was used to identify the key CRGs from hub CRGs. Transcriptional factors (TFs) and microRNAs (miRNAs) targeting hub CRGs were acquired from publicly available databases. The CIBERSORT algorithm was used to perform comparative immune cell infiltration analysis between normal and DN samples. RESULTS Eighty-two DECRGs were identified between normal and DN samples, as were 10 hub CRGs, namely PTGS2, DUSP1, JUN, FOS, S100A8, S100A12, NAIP, CLEC4E, CXCR1, and CXCR2. Thirty-nine TFs and 165 miRNAs potentially targeted these 10 hub CRGs. PTGS2 was identified as the key CRG and FOS as the most significant gene among all of DECRGs. RELA was identified as the hub TF interacting with PTGS2 by taking the intersection of potential TFs from the ChEA and JASPAR public databases. let-7b-5p was identified as the hub miRNA targeting PTGS2 by taking the intersection of miRNAs from the miRwalk, RNA22, RNAInter, TargetMiner, miRTarBase, and ENCORI databases. Similarly, CREB1, E2F1, and RELA were revealed as hub TFs for FOS, and miR-338-3p as the hub miRNA. Finally, compared with those in healthy samples, there are more infiltrating memory B cells, M1 macrophages, M2 macrophages, and resting mast cells and fewer infiltrating activated mast cells and neutrophils in DN samples (all p< 0.05). CONCLUSION The 10 identified hub copper-related genes provide insight into the mechanisms of DN development. It is beneficial to examine and understand the interaction between hub CRGs and potential regulatory molecules in DN. This knowledge may provide a novel theoretical foundation for the development of diagnostic biomarkers and copper-related therapy targets in DN.
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Affiliation(s)
- Jie Ming
- Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Si Ri Gu Leng Sana
- Department of Anaesthesiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- *Correspondence: Si Ri Gu Leng Sana,
| | - Xijin Deng
- Department of Anaesthesiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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Huang Y, Cheng J, Zhou Y, Zhang Y, Zhou S, Li Q, Peng L, Wang M, Song W, Wu G. Sulfuretted hydrogen ameliorates high dose glucose-induced podocyte apoptosis via orchestrating AMPK/mTOR cascade-mediated anti-apoptotic effects. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1586. [PMID: 34790792 PMCID: PMC8576736 DOI: 10.21037/atm-21-5152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 10/20/2021] [Indexed: 12/04/2022]
Abstract
Background Podocytes play a pivotal role in the glomerular filtration barrier and contribute to proteinuria and glomerulosclerosis through abnormal apoptosis. Longitudinal studies have indicated the protective properties of hydrogen sulfide (H2S) against neuronal cell apoptosis, whereas the biological function and the underlying molecular mechanism on glucose-induced podocyte apoptosis are largely unknown. Methods Herein, we conducted multifaceted biological analyses to verify the potential function of H2S in glucose-induced podocyte apoptosis by examining apoptotic proteins and markers (e.g., caspase 3, Hoechst) and antioxidative effects [e.g., reactive oxygen species (ROS), lipid peroxidation, superoxide dismutase (SOD), catalase (CAT)]. Then, we took advantage of transcriptome sequencing and biological analyses to further determine the potential influence of H2S as well as the accompanying molecular mechanism. Results In this study, we found that glucose-induced podocyte apoptosis could be largely rescued by H2S via antioxidative responses, which was further confirmed by transcriptome sequencing and bioinformatics analyses. According to apoptotic signaling analysis, the over-activated AMPK/mTOR signaling cascade in glucose-treated podocytes was effectively restrained. Conclusions For the first time, we indicated the protective effect and mechanism of H2S in podocytes by restricting glucose-induced apoptosis and suppressing the abnormally activated AMPK/mTOR signaling cascade. Our findings provide new references for podocyte apoptosis-associated diseases and also indicate the potential of H2S administration in clinical trials.
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Affiliation(s)
- Yong Huang
- Department of Nephrology, Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Jie Cheng
- Department of Nephrology, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Yehua Zhou
- Department of Nephrology, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Yanhui Zhang
- Department of Nephrology, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Shuhui Zhou
- Department of Nephrology, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Qingzhen Li
- Department of Nephrology, Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Lin Peng
- Department of Nephrology, Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Maohong Wang
- Department of Nephrology, Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Weiguo Song
- Department of Nephrology, Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Guoqing Wu
- Department of Nephrology, Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, China
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Xu X, Zhang L, Hua F, Zhang C, Zhang C, Mi X, Qin N, Wang J, Zhu A, Qin Z, Zhou F. FOXM1-activated SIRT4 inhibits NF-κB signaling and NLRP3 inflammasome to alleviate kidney injury and podocyte pyroptosis in diabetic nephropathy. Exp Cell Res 2021; 408:112863. [PMID: 34626587 DOI: 10.1016/j.yexcr.2021.112863] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 09/29/2021] [Accepted: 10/02/2021] [Indexed: 12/24/2022]
Abstract
Forkhead box M1 (FOXM1) has been reported to play a protective role against acute kidney injury by driving tubular regeneration. This study aims to probe the function of FOXM1 in diabetic nephropathy (DN) and the molecules involved. FOXM1 was poorly expressed in DN-diseased kidney tissues. A murine model of DN was established, and podocytes cells (MPC5) were treated with high-glucose (HG) for in vitro studies. FOXM1 overexpression improved kidney function and reduced pathological changes in mice, and it increased the expression of the podocyte marker Nephrin in kidney tissues. In vitro, FOXM1 increased viability and reduced pyroptosis of the HG-treated MPC5 cells, and it elevated the expression of the podocyte marker Nephrin whereas reduced the expression of pyroptosis-related NLRP3 inflammasome and cleaved caspase 1. FOXM1 bound to the promoter of sirtuin 4 (SIRT4) to induce transcriptional activation. Downregulation of SIRT4 blocked the protective roles of FOXM1 both in vivo and in vitro. Phosphorylation of nuclear factor-kappa B (NF-κB) in HG-treated cells was suppressed by FOXM1 but restored after SIRT4 inhibition. In conclusion, this study suggested that FOXM1 transcriptionally activates SIRT4 and inhibits NF-κB signaling and the NLRP3 inflammasome to alleviate kidney injury and podocyte pyroptosis in DN.
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Affiliation(s)
- Xiaohong Xu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy (Xuzhou Medical University), Xuzhou, 221004, Jiangsu, PR China; Department of Nephrology, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, 223800, Jiangsu, PR China; Department of Nephrology, Suqian Hospital, Nanjing Drum Tower Hospital Group, Suqian, 223800, Jiangsu, PR China; Department of Endocrinology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, PR China
| | - Liexiang Zhang
- Department of Neurosurgery, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, 223800, Jiangsu, PR China
| | - Fei Hua
- Department of Endocrinology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, PR China.
| | - Ce Zhang
- Department of Nephrology, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, 223800, Jiangsu, PR China; Department of Nephrology, Suqian Hospital, Nanjing Drum Tower Hospital Group, Suqian, 223800, Jiangsu, PR China
| | - Chi Zhang
- Department of Nephrology, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, 223800, Jiangsu, PR China; Department of Nephrology, Suqian Hospital, Nanjing Drum Tower Hospital Group, Suqian, 223800, Jiangsu, PR China
| | - Xia Mi
- Department of Nephrology, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, 223800, Jiangsu, PR China; Department of Nephrology, Suqian Hospital, Nanjing Drum Tower Hospital Group, Suqian, 223800, Jiangsu, PR China
| | - Nan Qin
- Department of Nephrology, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, 223800, Jiangsu, PR China; Department of Nephrology, Suqian Hospital, Nanjing Drum Tower Hospital Group, Suqian, 223800, Jiangsu, PR China
| | - Junsheng Wang
- Department of Nephrology, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, 223800, Jiangsu, PR China; Department of Nephrology, Suqian Hospital, Nanjing Drum Tower Hospital Group, Suqian, 223800, Jiangsu, PR China
| | - Aimin Zhu
- Department of Nephrology, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, 223800, Jiangsu, PR China; Department of Nephrology, Suqian Hospital, Nanjing Drum Tower Hospital Group, Suqian, 223800, Jiangsu, PR China
| | - Zihan Qin
- Department of Endocrinology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, PR China
| | - Feihong Zhou
- Department of Nephrology, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, 223800, Jiangsu, PR China; Department of Nephrology, Suqian Hospital, Nanjing Drum Tower Hospital Group, Suqian, 223800, Jiangsu, PR China
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TÜNCEL Ö, KARA M, YAYLAK B, ERDOĞAN İ, AKGÜL B. Noncoding RNAs in apoptosis: identification and function. Turk J Biol 2021; 46:1-40. [PMID: 37533667 PMCID: PMC10393110 DOI: 10.3906/biy-2109-35] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 02/08/2022] [Accepted: 11/14/2021] [Indexed: 08/04/2023] Open
Abstract
Apoptosis is a vital cellular process that is critical for the maintenance of homeostasis in health and disease. The derailment of apoptotic mechanisms has severe consequences such as abnormal development, cancer, and neurodegenerative diseases. Thus, there exist complex regulatory mechanisms in eukaryotes to preserve the balance between cell growth and cell death. Initially, protein-coding genes were prioritized in the search for such regulatory macromolecules involved in the regulation of apoptosis. However, recent genome annotations and transcriptomics studies have uncovered a plethora of regulatory noncoding RNAs that have the ability to modulate not only apoptosis but also many other biochemical processes in eukaryotes. In this review article, we will cover a brief summary of apoptosis and detection methods followed by an extensive discussion on microRNAs, circular RNAs, and long noncoding RNAs in apoptosis.
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Affiliation(s)
- Özge TÜNCEL
- Non-coding RNA Laboratory, Department of Molecular Biology and Genetics, Faculty of Science, İzmir Institute of Technology, İzmir,
Turkey
| | - Merve KARA
- Non-coding RNA Laboratory, Department of Molecular Biology and Genetics, Faculty of Science, İzmir Institute of Technology, İzmir,
Turkey
| | - Bilge YAYLAK
- Non-coding RNA Laboratory, Department of Molecular Biology and Genetics, Faculty of Science, İzmir Institute of Technology, İzmir,
Turkey
| | - İpek ERDOĞAN
- Non-coding RNA Laboratory, Department of Molecular Biology and Genetics, Faculty of Science, İzmir Institute of Technology, İzmir,
Turkey
| | - Bünyamin AKGÜL
- Non-coding RNA Laboratory, Department of Molecular Biology and Genetics, Faculty of Science, İzmir Institute of Technology, İzmir,
Turkey
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Du H, Zhang H, Yang R, Qiao L, Shao H, Zhang X. Small interfering RNA-induced silencing lncRNA PVT1 inhibits atherosclerosis via inactivating the MAPK/NF-κB pathway. Aging (Albany NY) 2021; 13:24449-24463. [PMID: 34775377 PMCID: PMC8610127 DOI: 10.18632/aging.203696] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 10/25/2021] [Indexed: 12/20/2022]
Abstract
Atherosclerosis (AS) is a chronic disease of the arterial wall. The role of lncRNAs in AS has been acknowledged. This study investigated the role of lncRNA plasmacytoma variant translocation 1 (PVT1) in AS via the MAPK/NF-κB pathway. Serum samples were collected from AS and non-AS patients. Serum levels of PVT1, CRP, IL-6, IL-1β, and TNF-α were determined. AS mouse model was established and transfected with si-PVT1. Levels of TG, TC, HDL, LDL, MAPK, NF-κB, MMP-2, MMP-9, TIMP-1, and macrophage content were detected. Human arterial vascular smooth muscle cells (HA-VSMCs) induced by 50 mg/mL oxLDL were transfected with si-PVT1 or oe-PVT1 and added with MAPK inhibitor U0126. Viability, apoptosis, cell cycle, colony formation and DNA replication were assessed. Levels of apoptosis-related proteins were detected. Consequently, PVT1 was highly expressed in AS patients. Silencing PVT1 decreased levels of TG, TC, LDL, IL-6, IL-1β, TNF-α, MMP-2, MMP-9, CRP, TIMP-1, MAPK, and NF-κB, increased HDL, reduced atherosclerotic plaques and macrophage content in mice, inhibited viability, clones and EdU positive rates in HA-VSMCs, but promoted apoptosis and cell cycle arrest. Inhibition of MAPK/NF-κB pathway suppressed proliferation and promoted apoptosis of HA-VSMCs while PVT1 overexpression facilitated AS development. Briefly, silencing PVT1 inhibited AS development by downregulating MAPK/NF-κB pathway.
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Affiliation(s)
- Hong Du
- Department of Cardiology, Second Hospital of Hebei Medical University, Shijiazhaung 050000, Hebei, P.R. China
| | - Hui Zhang
- Department of Cardiology, Second Hospital of Hebei Medical University, Shijiazhaung 050000, Hebei, P.R. China
| | - Rong Yang
- Department of Cardiology, Second Hospital of Hebei Medical University, Shijiazhaung 050000, Hebei, P.R. China
| | - Li Qiao
- Department of Cardiology, Second Hospital of Hebei Medical University, Shijiazhaung 050000, Hebei, P.R. China
| | - Huiyu Shao
- Department of Cardiology, Second Hospital of Hebei Medical University, Shijiazhaung 050000, Hebei, P.R. China
| | - Xiaolin Zhang
- Department of Cardiology, Second Hospital of Hebei Medical University, Shijiazhaung 050000, Hebei, P.R. China
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Wang T, Wen X, Zhang Z, Xie M, Zhou J. Phillyrin ameliorates diabetic nephropathy through the PI3K/Akt/GSK-3β signalling pathway in streptozotocin-induced diabetic mice. Hum Exp Toxicol 2021; 40:S487-S496. [PMID: 34649470 DOI: 10.1177/09603271211051598] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Diabetic nephropathy is a progressive kidney disease resulting from long-term hyperglycaemia in diabetic patients, and the underlying mechanism is complex and lacks effective treatments. Various active ingredients in Chinese herbs have been shown to alleviate renal injury and improve DN in recent years. Phillyrin, a natural medicinal active compound extracted from the Oleaceae family, has various pharmacological effects, including antioxidative, antiapoptotic and antiobesity effects. However, the role of phillyrin and its underlying mechanism in DN have not yet been explored. To investigate the effects of phillyrin on DN and its potential mechanisms of action, we performed experiments using streptozotocin (STZ)-induced DN mice as models. Phillyrin significantly reduced the levels of fasting blood glucose (FBG) and glycosylated haemoglobin A1c (HbA1c), downregulated the levels of serum blood urea nitrogen (BUN), serum creatinine (Scr), serum and urine β2-microglobulins (β2-MG) and improved the pathological changes of the kidney in a DN mouse model. Phillyrin also increased the level of antioxidants and attenuated oxidative damage in DN model mice. In addition, phillyrin inhibited Glycogen synthase kinase-3β (GSK-3β) activity by activating the PI3K/Akt signalling pathway, increased the Bcl-2/Bax ratio, reduced the release of cytochrome c from the mitochondria to the cytoplasm, subsequently inhibited the activation of caspase-3 and ultimately suppressed renal cell apoptosis. These findings suggested that phillyrin could be a new promising therapeutic strategy for DN, and this protective effect might be related to suppressing oxidative stress and apoptosis via the PI3K/Akt/GSK-3β pathway.
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Affiliation(s)
- Tianyang Wang
- School of Medicine, 117771Yichun University, Yichun, P.R. China
| | - Xuejiao Wen
- School of Medicine, 117771Yichun University, Yichun, P.R. China
| | - Ziwen Zhang
- School of Medicine, 117771Yichun University, Yichun, P.R. China
| | - Minjuan Xie
- School of Medicine, 117771Yichun University, Yichun, P.R. China
| | - Jie Zhou
- School of Medicine, 117771Yichun University, Yichun, P.R. China
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Alipoor B, Nikouei S, Rezaeinejad F, Malakooti-Dehkordi SN, Sabati Z, Ghasemi H. Long non-coding RNAs in metabolic disorders: pathogenetic relevance and potential biomarkers and therapeutic targets. J Endocrinol Invest 2021; 44:2015-2041. [PMID: 33792864 DOI: 10.1007/s40618-021-01559-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 03/22/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND It has been suggested that dysregulation of long non-coding RNAs (lncRNAs) could be associated with the incidence and development of metabolic disorders. AIM Accordingly, this narrative review described the molecular mechanisms of lncRNAs in the development of metabolic diseases including insulin resistance, diabetes, obesity, non-alcoholic fatty liver disease (NAFLD), cirrhosis, and coronary artery diseases (CAD). Furthermore, we investigated the up-to-date findings on the association of deregulated lncRNAs in the metabolic disorders, and potential use of lncRNAs as biomarkers and therapeutic targets. CONCLUSION LncRNAs/miRNA/regulatory proteins axis plays a crucial role in progression of metabolic disorders and may be used in development of therapeutic and diagnostic approaches.
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Affiliation(s)
- B Alipoor
- Department of Laboratory Sciences, Faculty of Paramedicine, Yasuj University of Medical Sciences, Yasuj, Iran
| | - S Nikouei
- Student Research Committee, Yasuj University of Medical Sciences, Yasuj, Iran
| | - F Rezaeinejad
- Department of Biochemistry, Faculty of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran
| | | | - Z Sabati
- MSc student of Hematology, Student Research Committee, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran
| | - H Ghasemi
- Abadan Faculty of Medical Sciences, Abadan, Iran.
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Abstract
Epigenetics examines heritable changes in DNA and its associated proteins except mutations in gene sequence. Epigenetic regulation plays fundamental roles in kidney cell biology through the action of DNA methylation, chromatin modification via epigenetic regulators and non-coding RNA species. Kidney diseases, including acute kidney injury, chronic kidney disease, diabetic kidney disease and renal fibrosis are multistep processes associated with numerous molecular alterations even in individual kidney cells. Epigenetic alterations, including anomalous DNA methylation, aberrant histone alterations and changes of microRNA expression all contribute to kidney pathogenesis. These changes alter the genome-wide epigenetic signatures and disrupt essential pathways that protect renal cells from uncontrolled growth, apoptosis and development of other renal associated syndromes. Molecular changes impact cellular function within kidney cells and its microenvironment to drive and maintain disease phenotype. In this chapter, we briefly summarize epigenetic mechanisms in four kidney diseases including acute kidney injury, chronic kidney disease, diabetic kidney disease and renal fibrosis. We primarily focus on current knowledge about the genome-wide profiling of DNA methylation and histone modification, and epigenetic regulation on specific gene(s) in the pathophysiology of these diseases and the translational potential of identifying new biomarkers and treatment for prevention and therapy. Incorporating epigenomic testing into clinical research is essential to elucidate novel epigenetic biomarkers and develop precision medicine using emerging therapies.
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Xia W, He Y, Gan Y, Zhang B, Dai G, Ru F, Jiang Z, Chen Z, Chen X. Long Non-coding RNA: An Emerging Contributor and Potential Therapeutic Target in Renal Fibrosis. Front Genet 2021; 12:682904. [PMID: 34386039 PMCID: PMC8353329 DOI: 10.3389/fgene.2021.682904] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 06/28/2021] [Indexed: 12/19/2022] Open
Abstract
Renal fibrosis (RF) is a pathological process that culminates in terminal renal failure in chronic kidney disease (CKD). Fibrosis contributes to progressive and irreversible decline in renal function. However, the molecular mechanisms involved in RF are complex and remain poorly understood. Long non-coding RNAs (lncRNAs) are a major type of non-coding RNAs, which significantly affect various disease processes, cellular homeostasis, and development through multiple mechanisms. Recent investigations have implicated aberrantly expressed lncRNA in RF development and progression, suggesting that lncRNAs play a crucial role in determining the clinical manifestation of RF. In this review, we comprehensively evaluated the recently published articles on lncRNAs in RF, discussed the potential application of lncRNAs as diagnostic and/or prognostic biomarkers, proposed therapeutic targets for treating RF-associated diseases and subsequent CKD transition, and highlight future research directions in the context of the role of lncRNAs in the development and treatment of RF.
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Affiliation(s)
- Weiping Xia
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
| | - Yao He
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
| | - Yu Gan
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
| | - Bo Zhang
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
| | - Guoyu Dai
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
| | - Feng Ru
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
| | - Zexiang Jiang
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
| | - Zhi Chen
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
| | - Xiang Chen
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
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Zhao P, Malik S, Xing S. Epigenetic Mechanisms Involved in HCV-Induced Hepatocellular Carcinoma (HCC). Front Oncol 2021; 11:677926. [PMID: 34336665 PMCID: PMC8320331 DOI: 10.3389/fonc.2021.677926] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 06/28/2021] [Indexed: 12/19/2022] Open
Abstract
Hepatocellular carcinoma (HCC), is the third leading cause of cancer-related deaths, which is largely caused by virus infection. About 80% of the virus-infected people develop a chronic infection that eventually leads to liver cirrhosis and hepatocellular carcinoma (HCC). With approximately 71 million HCV chronic infected patients worldwide, they still have a high risk of HCC in the near future. However, the mechanisms of carcinogenesis in chronic HCV infection have not been still fully understood, which involve a complex epigenetic regulation and cellular signaling pathways. Here, we summarize 18 specific gene targets and different signaling pathways involved in recent findings. With these epigenetic alterations requiring histone modifications and DNA hyper or hypo-methylation of these specific genes, the dysregulation of gene expression is also associated with different signaling pathways for the HCV life cycle and HCC. These findings provide a novel insight into a correlation between HCV infection and HCC tumorigenesis, as well as potentially preventable approaches. Hepatitis C virus (HCV) infection largely causes hepatocellular carcinoma (HCC) worldwide with 3 to 4 million newly infected cases diagnosed each year. It is urgent to explore its underlying molecular mechanisms for therapeutic treatment and biomarker discovery. However, the mechanisms of carcinogenesis in chronic HCV infection have not been still fully understood, which involve a complex epigenetic regulation and cellular signaling pathways. Here, we summarize 18 specific gene targets and different signaling pathways involved in recent findings. With these epigenetic alterations requiring histone modifications and DNA hyper or hypo-methylation of these specific genes, the dysregulation of gene expression is also associated with different signaling pathways for the HCV life cycle and HCC. These findings provide a novel insight into a correlation between HCV infection and HCC tumorigenesis, as well as potentially preventable approaches.
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Affiliation(s)
- Pin Zhao
- Guandong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Health Science Center, Shenzhen, China
| | - Samiullah Malik
- Department of Pathogen Biology, Shenzhen University Health Science Center, Shenzhen, China
| | - Shaojun Xing
- Department of Pathogen Biology, Shenzhen University Health Science Center, Shenzhen, China
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Wang YZ, Yao-Li, Liang SK, Ding LB, Feng-Li, Guan J, Wang HJ. LncPVT1 promotes cartilage degradation in diabetic OA mice by downregulating miR-146a and activating TGF-β/SMAD4 signaling. J Bone Miner Metab 2021; 39:534-546. [PMID: 33569722 DOI: 10.1007/s00774-020-01199-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 12/14/2020] [Indexed: 10/22/2022]
Abstract
INTRODUCTION To investigate the role of LncRNA PVT1 (plasmacytoma variant translocation 1) in hyperglycemia-triggered cartilage damage using the diabetic osteoarthritis (OA) mice model. MATERIALS AND METHODS Streptozotocin (STZ) was used to induce mouse diabetes. Knee OA model was induced through transection of anterior cruciate ligament (ACLT). Severity of arthritis was assessed histologically by Safranin O-Fast Green Staining using Mankin Scores. LncRNA PVT1 and miR-146a were detected by real-time polymerase chain reaction (PCR) in cartilage tissue. Moreover, the interaction among PVT1, miR-146a, and SMAD4 was examined by luciferase reporter assays. Mice were injected intra-articularly with ad-siRNA-PVT1 and ad-siRNA scramble control. Articular concentrations of TNF-α, IL-1, IL-6 and TGF-β1 were determined using enzyme-linked immunosorbent assay. Levels of type II Collagen (COL2A1), TGF-β1, p-SMAD2, SMAD2, p-SMAD3, SMAD3, SMAD4 and nuclear SMAD4 were detected by western blot analysis. RESULTS PVT1 expression was significantly increased, whereas miR-146a was markedly decreased in diabetic OA mice than in non-diabetic OA and control. Increased PVT1 expression in diabetic OA mice was significantly associated with Mankin score and reduced miR-146a as well as Collagen alpha-1(II) (COL2A1) expressions. In vivo, intra-articular injection of ad-siRNA-PVT1 efficiently increased miR-146a and COL2A1 expressions, alleviated joint inflammation, decreased the expression of pro-inflammatory mediators, and suppressed TGF-β/SMAD4 pathway in diabetic OA mice. CONCLUSIONS Our results demonstrate LncRNA PVT1 is involved in cartilage degradation in diabetic OA and correlated with disease severity. Efficiency of ad-siRNA-PVT1 in controlling joint inflammation in diabetic OA mice is associated with the suppression of the expression of miR-146a, pro-inflammatory cytokines and activation of TGF-β/SMAD4 pathway.
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Affiliation(s)
- Yan-Zhi Wang
- Department of Orthopedic Surgery, Third Hospital of Shijiazhuang, ChangAn District, , Shijiazhuang, 050011, HeBei, China
| | - Yao-Li
- Department of Orthopedic Surgery, Third Hospital of Shijiazhuang, ChangAn District, , Shijiazhuang, 050011, HeBei, China
| | - Sheng-Kai Liang
- Department of Orthopedic Surgery, Third Hospital of Shijiazhuang, ChangAn District, , Shijiazhuang, 050011, HeBei, China
| | - Luo-Bin Ding
- Department of Orthopedic Surgery, Third Hospital of Shijiazhuang, ChangAn District, , Shijiazhuang, 050011, HeBei, China
| | - Feng-Li
- Department of Orthopedic Surgery, Third Hospital of Shijiazhuang, ChangAn District, , Shijiazhuang, 050011, HeBei, China
| | - Jian Guan
- Department of Orthopedic Surgery, Third Hospital of Shijiazhuang, ChangAn District, , Shijiazhuang, 050011, HeBei, China.
| | - Hua-Jun Wang
- Department of Orthopedic Surgery and Sports Medicine Center, The First Affiliated Hospital of Jinan University, Road West No. 613, Huang-Pu, Guangzhou, 510632, GuangDong, China.
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Su WY, Li Y, Chen X, Li X, Wei H, Liu Z, Shen Q, Chen C, Wang YP, Li W. Ginsenoside Rh1 Improves Type 2 Diabetic Nephropathy through AMPK/PI3K/Akt-Mediated Inflammation and Apoptosis Signaling Pathway. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2021; 49:1215-1233. [PMID: 34049473 DOI: 10.1142/s0192415x21500580] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Although ginseng (Panax ginseng C.A. Meyer) has received extensive attention in the treatment and prevention of type 2 diabetes mellitus (T2DM) in the past few decades, there are few studies on the complications of T2DM. At present, obesity-linked diabetic nephropathy (DN) has become the most prevailing element of the end-stage renal failure in the world. The aim of this work is to evaluate the ameliorative effects of ginsenoside Rh1 (G-Rh1) on DN induced by high fat diet plus streptozotocin (HFD/STZ) through some potential and combined mechanisms of action. The results showed that G-Rh1 treatment at 5 and 10 mg/kg for 8 weeks exerted excellent effects in controlling fasting blood glucose (FBG), improving glucose tolerance, and increasing insulin level. In addition, G-Rh1 effectively prevents the excessive production of advanced glycation end products (AGEs), a diabetic nephropathy marker, in HFD/STZ induced DN mice. Meanwhile, oxidation indicators including SOD, GSH, and MDA were improved by G-Rh1 treatment to varying degrees. It is worth noting that G-Rh1 not only inhibits the secretion of Nox1 and Nox4 in kidney tissues, but also has an inhibitory effect on inflammatory factors and NF-[Formula: see text]B signaling pathway. Importantly, further in-depth research on molecular mechanisms provides vital evidence that the ameliorative effect of G-Rh1 on DN is related to the inhibition of apoptosis and the AMPK/PI3K/Akt signaling pathway. In summary, G-Rh1 may be of great value in improving the treatment of DN although more experimental data is needed.
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Affiliation(s)
- Wen-Ya Su
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, P. R. China
| | - Ying Li
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, P. R. China
| | - Xuan Chen
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, P. R. China
| | - Xin Li
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, P. R. China
| | - Heng Wei
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, P. R. China
| | - Zhi Liu
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, P. R. China.,National & Local Joint Engineering Research Center for Ginseng Breeding and Development, Changchun 130118, P. R. China
| | - Qiong Shen
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, P. R. China
| | - Chen Chen
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Ying-Ping Wang
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, P. R. China.,National & Local Joint Engineering Research Center for Ginseng Breeding and Development, Changchun 130118, P. R. China
| | - Wei Li
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, P. R. China.,National & Local Joint Engineering Research Center for Ginseng Breeding and Development, Changchun 130118, P. R. China
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