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Donate-Correa J, González-Luis A, Díaz-Vera J, Hernandez-Fernaud JR. MicroRNA-630: A promising avenue for alleviating inflammation in diabetic kidney disease. World J Diabetes 2024; 15:1398-1403. [PMID: 39099820 PMCID: PMC11292322 DOI: 10.4239/wjd.v15.i7.1398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Revised: 03/18/2024] [Accepted: 04/22/2024] [Indexed: 07/08/2024] Open
Abstract
Diabetic kidney disease (DKD) is one of the complications of diabetes, affecting millions of people worldwide. The relentless progression of this condition can lead to kidney failure, requiring life-altering interventions such as dialysis or transplants. Accumulating evidence suggests that immunologic and inflammatory elements play an important role in initiating and perpetuating the damage inflicted on renal tissues, exacerbating the decline in organ function. Toll-like receptors (TLRs) are a family of receptors that play a role in the activation of the innate immune system by the recognition of pathogen-associated molecular patterns. Recent data from in vitro and in vivo studies have highlighted the critical role of TLRs, mainly TLR2 and TLR4, in the pathogenesis of DKD. In the diabetic milieu, these TLRs recognize diabetic-associated molecular signals, triggering a proinflammatory cascade that initiates and perpetuates inflammation and fibrogenesis in the diabetic kidney. Emerging non-traditional strategies targeting TLR signaling with potential therapeutic implications in DKD have been pro-posed. One of these approaches is the use of microRNAs, small non-coding RNAs that can regulate gene expression. This editorial comments on the results of this approach carried out in a rat model of diabetes by Wu et al, published in this issue of the World Journal of Diabetes. The results of the experimental study by Wu et al shows that microRNA-630 decreased levels compared to non-diabetic rats. Additionally, microRNA-630 exerted anti-inflammatory effects in the kidneys of diabetic rats through the modulation of TLR4. These findings indicate that the microRNA-630/TLR4 axis might represent a pathological mechanism of DKD and a potential therapeutic target capable of curbing the destructive inflammation characteristic of DKD.
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Affiliation(s)
- Javier Donate-Correa
- Research Unit, University Hospital Nuestra Señora de Candelaria (UHNSC), Santa Cruz de Tenerife 38010, Spain
| | - Ainhoa González-Luis
- Research Unit, University Hospital Nuestra Señora de Candelaria (UHNSC), Santa Cruz de Tenerife 38010, Spain
| | - Jésica Díaz-Vera
- Research Unit, University Hospital Nuestra Señora de Candelaria (UHNSC), Santa Cruz de Tenerife 38010, Spain
| | - Juan Ramón Hernandez-Fernaud
- Department of Biochemistry, Microbiology, Cell Biology and Genetics, Instituto de Tecnologías Biomédicas, Universidad de La Laguna, Santa Cruz de Tenerife 38000, Spain
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Zhang Z, Zhang X, Gao X, Fang B, Tian S, Kang P, Zhao Y. MiR-150-5p Alleviates Renal Tubule Epithelial Cell Fibrosis via the Inhibition of Epithelial-Mesenchymal Transition by Targeting ZEB1. Int Arch Allergy Immunol 2024; 185:827-835. [PMID: 38763133 DOI: 10.1159/000538670] [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: 02/15/2024] [Accepted: 03/28/2024] [Indexed: 05/21/2024] Open
Abstract
INTRODUCTION Although microRNA (miR)-150-5p participates in the progression of renal fibrosis, its mechanism of action remains elusive. METHODS A mouse model of unilateral ureteral obstruction was used. The in vitro renal fibrosis model was established by stimulating human kidney 2 (HK-2) cells with transforming growth factor beta 1 (TGF-β1). The expression profiles of miR-150-5p, zinc finger E-box binding homeobox 1 (ZEB1), and other fibrosis- and epithelial-mesenchymal transition (EMT)-linked proteins were determined using Western blot and quantitative reverse transcription polymerase chain reaction. The relationship between miR-150-5p and ZEB1 in HK-2 cells was confirmed by a dual-luciferase reporter assay. RESULTS Both in vivo and in vitro renal fibrosis models revealed reduced miR-150-5p expression and elevated ZEB1 level. A significant decrease in E-cadherin levels, as well as increases in alpha smooth muscle actin (α-SMA) and collagen type I (Col-I) levels, was seen in TGF-β1-treated HK-2 cells. The overexpression of miR-150-5p ameliorated TGF-β1-mediated fibrosis and EMT. Notably, miR-150-5p acts by directly targeting ZEB1. A significant reversal of the inhibitory impact of miR-150-5p on TGF-β1-mediated fibrosis and EMT in HK-2 cells was observed upon ZEB1 overexpression. CONCLUSION MiR-150-5p suppresses TGF-β1-induced fibrosis and EMT by targeting ZEB1 in HK-2 cells, providing helpful insights into the therapeutic intervention of renal fibrosis.
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Affiliation(s)
- Zhizhong Zhang
- Department of Urology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, China
| | - Xinyu Zhang
- Department of Stomatology, Yinchuan Guolong Hospital, Yinchuan, China
| | - Xiangming Gao
- Department of Obstetrics and Gynecology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, China
| | - Bing Fang
- Department of General Medicine, Yinchuan Meinian Health Hospital, Yinchuan, China
| | - Shuyu Tian
- Internal Medicine, Yinchuan Guolong Hospital, Yinchuan, China
| | - Ping Kang
- Department of Surgery, Yinchuan Guolong Hospital, Yinchuan, China
| | - Yi Zhao
- Department of Urology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, China
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CircRNA SCMH1 regulates the miR-200a-3p/ZEB1 signaling axis to promote diabetes-induced retinal epithelial-mesenchymal transition. Exp Eye Res 2022; 224:109264. [PMID: 36162459 DOI: 10.1016/j.exer.2022.109264] [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: 01/11/2022] [Revised: 08/23/2022] [Accepted: 09/19/2022] [Indexed: 11/22/2022]
Abstract
Diabetic retinopathy (DR) is one of the common systemic complications of diabetes. Epithelial-mesenchymal transition (EMT) is required for DR progression. Previous studies have explored that circular RNAs (circRNAs) are crucial for DR development. Herein, we focused on the biological functions of circSCMH1 in DR. RT-qPCR determined the expression of circSCMH1, miR-200a-3p and ZEB1. EMT-related proteins were measured by Western blot. Gene combinations were validated by RIP and dual luciferase reporter assays. CCK-8, EdU, TUNEL staining and Transwell analysis were used to assess the cellular function. FISH analysis assessed the localization of circSCMH1 and miR-200a-3p. HE staining was used to detect retinal structures in a mouse DR model. High-glucose (HG) significantly increased circSCMH1 expression in ARPE-19 cells. Additionally, circSCMH1 silencing repressed proliferation, migration, and EMT in HG cells. Mechanistically, circSCMH1 positively regulated ZEB1 expression via targeting miR-200a-3p. Furthermore, circSCMH1 was observed to induce HG cell growth and EMT by regulating the miR-200a-3p/ZEB1 axis. Finally, we verified that downregulation of circSCMH1 or ZEB1 alleviated EMT in the retina of diabetic mice. These findings have implications for new therapeutic targets for DR.
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Xiao L, Chen A, Gao Q, Xu B, Guo X, Guan T. Pentosan polysulfate ameliorates fibrosis and inflammation markers in SV40 MES13 cells by suppressing activation of PI3K/AKT pathway via miR-446a-3p. BMC Nephrol 2022; 23:105. [PMID: 35291969 PMCID: PMC8925175 DOI: 10.1186/s12882-022-02732-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 03/08/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Renal fibrosis is a common outcome of various renal damage, including diabetic nephropathy (DN), the leading cause of end-stage renal disease. Currently, there are no effective therapies for renal fibrosis. The present study aimed to determine whether pentosan polysulphate sodium (PPS), a FDA approved medication for interstitial cystitis, protects diabetic renal fibrosis. METHODS Cell viability and apoptosis were evaluated in mouse mesangial cells (SV40-MES13) after incubating with the advanced glycation end products (AGEs), which play important roles in the pathogenesis of DN. Western blot and ELISA were performed to determine the expression of transforming growth factor-beta1 (TGF-β1) and fibronectin (FN), two biomarkers of renal fibrosis, as well as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα), two biomarkers of inflammation. The miRNA-mRNA regulatory network involved in the phosphatidylinositol 3-kinase (PI3K)/Ser and Thr Kinase (AKT) signalling was investigated by miRNA deep sequencing and validated by RT-PCR and miRNA transfection. RESULTS AGEs significantly inhibited cell proliferation and promoted cell apoptosis, which was associated with the overexpression of TGF-β1, FN, IL-6, and TNFα. PPS almost completely reversed AGEs-induced biomarkers of fibrosis and inflammation, and significantly altered the miRNA expression profile in AGEs-treated cells. Notably, the PI3K/AKT signalling was one of the most significantly enriched pathways targeted by PPS-related differentially expressed miRNAs. PPS significantly up-regulated miR-466a-3p, which was shown to target PIK3CA, and mediated the inhibitory effect of PPS on AGEs-induced activation of PI3K/AKT pathway. CONCLUSIONS The treatment of PPS protected against AGEs-induced toxicity in SV40 MES13 cells via miR-466a-3p-mediated inhibition of PI3K/AKT pathway.
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Affiliation(s)
- Liangxiang Xiao
- Department of Nephrology, Zhongshan Hospital of Xiamen University, School of Medicine, Xamen University, No 203, Hubin South Road, Siming district, Xiamen, 361004, Fujian, China
| | - Anqun Chen
- Department of Nephrology, Zhongshan Hospital of Xiamen University, School of Medicine, Xamen University, No 203, Hubin South Road, Siming district, Xiamen, 361004, Fujian, China
| | - Qing Gao
- Department of Nephrology, Zhongshan Hospital of Xiamen University, School of Medicine, Xamen University, No 203, Hubin South Road, Siming district, Xiamen, 361004, Fujian, China
| | - Bo Xu
- Department of Nephrology, Zhongshan Hospital of Xiamen University, School of Medicine, Xamen University, No 203, Hubin South Road, Siming district, Xiamen, 361004, Fujian, China
| | - Xiaodan Guo
- Department of Nephrology, Zhongshan Hospital of Xiamen University, School of Medicine, Xamen University, No 203, Hubin South Road, Siming district, Xiamen, 361004, Fujian, China
| | - Tianjun Guan
- Department of Nephrology, Zhongshan Hospital of Xiamen University, School of Medicine, Xamen University, No 203, Hubin South Road, Siming district, Xiamen, 361004, Fujian, China.
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Dai Y, Guo M, Jiang L, Gao J. Network pharmacology-based identification of miRNA expression of Astragalus membranaceus in the treatment of diabetic nephropathy. Medicine (Baltimore) 2022; 101:e28747. [PMID: 35119030 PMCID: PMC8812605 DOI: 10.1097/md.0000000000028747] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 01/10/2022] [Indexed: 01/04/2023] Open
Abstract
Diabetic nephropathy (DN) is a common microvascular complication of diabetic patients, along with hypertension, hyperlipemia, proteinuria, edema, and other clinical manifestations. Astragalus membranaceus (AM) is a traditional Chinese medicine and has shown significant clinical efficacy against DN. However, the overall molecular mechanism of this therapeutic effect has not been entirely elucidated. Using network pharmacology, we aimed to identify the key active ingredients and potential pharmacological mechanisms of AM in treating DN and provide scientific evidence of its clinical efficacy.The active ingredients of AM were obtained from the traditional Chinese medicine systems pharmacology database, and the potential targets of AM were identified using the therapeutic target database. DN-related target genes were acquired from the Gene Expression Omnibus microarray dataset GSE1009 and 3 widely used databases-DisGeNET, GeneCards, and Comparative Toxicogenomics Database. The DN-AM common target protein interaction network was established by using the STRING database. Active ingredients candidate targets proteins networks were constructed using Cytoscape software for visualization. Additionally, gene ontology (GO) and Kyoto encyclopedia of genes and genomes pathway analyses were performed using the Database for Annotation, Visualization, and Integrated Discovery database. Target-regulating microRNAs (miRNAs) of these hub genes were obtained from the therapeutic target database, which could then be used for further identification of AM-regulated key miRNAs.A total of 17 active ingredients and 214 target proteins were screened from AM. 61 candidate co-expressed genes with therapeutic effects against DN were obtained and considered as potential therapeutic targets. GO and Kyoto encyclopedia of genes and genomes enrichment analysis showed that these genes were mainly involved in inflammatory response, angiogenesis, oxidative stress reaction, HIF signaling pathway, tumor necrosis factor signaling pathway, and VEGF signaling pathway. In all, 636 differentially expressed genes were identified between the DN patients and control group by using microarray data, GSE1009. Lastly, VEGFA, epidermal growth factor receptor, STAT1, and GJA1 were screened as hub genes. The relationships between miRNAs and hub genes were constructed, which showed that miR-302-3p, miR-372-3p, miR-373-3p, and miR-520-3p were regulated by VEGFA and epidermal growth factor receptor. Meanwhile, VEGFA also influenced miR-15-5p, miR-16-5p, miR-17-5p, miR-20-5p, miR-93-5p, miR-106-5p, miR-195-5p, miR-424-5p, miR-497-5p, and miR-519-3p. In addition, miR-1-3p and miR-206 were regulated by VEGFA and GJA1, and miR-23-3p was regulated by STAT1 and GJA1.To our knowledge, this study revealed for the first time the characteristic multiple components, multiple targets, and multiple pathways of AM that seem to be the underlying mechanisms of action of AM in the treatment of DN with respect to miRNAs.Private information from individuals will not be published. This systematic review also does not involve endangering participant rights. Ethical approval will not be required. The results may be published in a peer-reviewed journal or disseminated at relevant conferences.
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Affiliation(s)
- Yaji Dai
- Department of Pharmacy, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui, China
| | - Mingfei Guo
- Department of Pharmacy, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Lei Jiang
- Department of Pharmacy, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui, China
| | - Jiarong Gao
- Department of Pharmacy, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China
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Li X, Li N, Li B, Feng Y, Zhou D, Chen G. Noncoding RNAs and RNA-binding proteins in diabetic wound healing. Bioorg Med Chem Lett 2021; 50:128311. [PMID: 34438011 DOI: 10.1016/j.bmcl.2021.128311] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 08/02/2021] [Accepted: 08/04/2021] [Indexed: 12/15/2022]
Abstract
Poor wound healing is a common complication in diabetic patients. It often leads to intractable infections and lower limb amputations and is associated with cardiovascular morbidity and mortality. NcRNAs, which can regulate gene expression, have emerged as important regulators of various physiological processes. Herein, we summarize the diverse roles of ncRNAs in the key stages of diabetic wound healing, including inflammation, angiogenesis, re-epithelialization, and extracellular matrix remodeling. Meanwhile, the potential use of ncRNAs as novel therapeutic targets for wound healing in diabetic patients is also discussed. In addition, we summarize the role of RNA-binding proteins (RBPs) in the regulation of gene expression and signaling pathways during skin repair, which may provide opportunities for therapeutic intervention for this potentially devastating disease. However, so far, research on the modulated drug based on ncRNAs that lead to significantly altered gene expression in diabetic patients is scarce. We have compiled some drugs that may be able to modulate ncRNAs, which significantly regulate the gene expression in diabetic patients.
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Affiliation(s)
- Xue Li
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Ning Li
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Bingxin Li
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Yuan Feng
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China
| | - Di Zhou
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
| | - Gang Chen
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, People's Republic of China; Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, People's Republic of China.
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Exosomes derived from induced pluripotent stem cells suppresses M2-type macrophages during pulmonary fibrosis via miR-302a-3p/TET1 axis. Int Immunopharmacol 2021; 99:108075. [PMID: 34435585 DOI: 10.1016/j.intimp.2021.108075] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 08/09/2021] [Accepted: 08/11/2021] [Indexed: 02/07/2023]
Abstract
Idiopathic pulmonary fibrosis (PF) is a type of chronic lung disease. Here, we investigated the effect of induced pluripotent stem cell (iPSC)-derived exosomes (iPSC-exosomes) on M2-type macrophages which play a critical role in pulmonary fibrosis. Exosomes were purified from the conditioned medium of iPSCs. Mice models of pulmonary fibrosis were established by intratracheal instillation with 5 mg/kg bleomycin. Thereafter, the histopathological changes and collagen deposition were detected by HE and masson staining. Meanwhile the level of M2-type macrophages was elevated by immunofluorescence staining with F4/80 and Arg-1. Luciferase reporter assay was conducted to verify the binding of miR-302a-3p to ten-eleven translocation 1 (TET1). Our results showed that, after treatment with iPSC-exosomes, the pulmonary fibrosis induced by bleomycin was relieved, with less collagen deposition. In addition, the increased M2-type macrophages in PF mice were reduced upon treatment with iPSC-exosomes. Moreover, we found that the iPSC-exosomes showed higher level of miR-302a-3p. Interestingly, the level of miR-302a-3p in the lungs of PF mice was increased upon treatment with iPSC-exosomes. Furthermore, we verified that TET1 was a direct target of miR-302a-3p. Up-regulation of miR-302a-3p or TET1 silencing repressed M2-type macrophages. Down-regulation of miR-302a-3p abolished the beneficial effects of iPSC-exosomes on pulmonary fibrosis. Collectively, our study revealed that iPSC-exosomes delivered miR-302a-3p to suppress the M2-type macrophages via targeting TET1, thus mitigating pulmonary fibrosis. This study indicates that iPSC-exosomes may become a potential therapeutic agent for pulmonary fibrosis.
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Miranda MZ, Lichner Z, Szászi K, Kapus A. MRTF: Basic Biology and Role in Kidney Disease. Int J Mol Sci 2021; 22:ijms22116040. [PMID: 34204945 PMCID: PMC8199744 DOI: 10.3390/ijms22116040] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 05/21/2021] [Accepted: 05/30/2021] [Indexed: 12/23/2022] Open
Abstract
A lesser known but crucially important downstream effect of Rho family GTPases is the regulation of gene expression. This major role is mediated via the cytoskeleton, the organization of which dictates the nucleocytoplasmic shuttling of a set of transcription factors. Central among these is myocardin-related transcription factor (MRTF), which upon actin polymerization translocates to the nucleus and binds to its cognate partner, serum response factor (SRF). The MRTF/SRF complex then drives a large cohort of genes involved in cytoskeleton remodeling, contractility, extracellular matrix organization and many other processes. Accordingly, MRTF, activated by a variety of mechanical and chemical stimuli, affects a plethora of functions with physiological and pathological relevance. These include cell motility, development, metabolism and thus metastasis formation, inflammatory responses and—predominantly-organ fibrosis. The aim of this review is twofold: to provide an up-to-date summary about the basic biology and regulation of this versatile transcriptional coactivator; and to highlight its principal involvement in the pathobiology of kidney disease. Acting through both direct transcriptional and epigenetic mechanisms, MRTF plays a key (yet not fully appreciated) role in the induction of a profibrotic epithelial phenotype (PEP) as well as in fibroblast-myofibroblast transition, prime pathomechanisms in chronic kidney disease and renal fibrosis.
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Affiliation(s)
- Maria Zena Miranda
- Keenan Research Centre for Biomedical Science of the St. Michael’s Hospital, Toronto, ON M5B 1W8, Canada; (M.Z.M.); (Z.L.); (K.S.)
| | - Zsuzsanna Lichner
- Keenan Research Centre for Biomedical Science of the St. Michael’s Hospital, Toronto, ON M5B 1W8, Canada; (M.Z.M.); (Z.L.); (K.S.)
| | - Katalin Szászi
- Keenan Research Centre for Biomedical Science of the St. Michael’s Hospital, Toronto, ON M5B 1W8, Canada; (M.Z.M.); (Z.L.); (K.S.)
- Department of Surgery, University of Toronto, Toronto, ON M5T 1P5, Canada
| | - András Kapus
- Keenan Research Centre for Biomedical Science of the St. Michael’s Hospital, Toronto, ON M5B 1W8, Canada; (M.Z.M.); (Z.L.); (K.S.)
- Department of Surgery, University of Toronto, Toronto, ON M5T 1P5, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada
- Correspondence:
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MiR-467a-5p aggravates myocardial infarction by modulating ZEB1 expression in mice. J Mol Histol 2021; 52:767-780. [PMID: 33997926 DOI: 10.1007/s10735-021-09978-w] [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: 01/28/2021] [Accepted: 05/04/2021] [Indexed: 12/19/2022]
Abstract
Myocardial infarction (MI) is a great threat to patients all over the word. MicroRNAs (miRNAs) are a group of non-coding RNAs and can regulate initiation and progression of MI. The current research aimed to investigate the role of miR-467a-5p in MI. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was conducted to detective relative expression of miR-467a-5p in cardiac tissues and mouse cardiomyocytes (MCMs). Hematoxylin and eosin staining was used to reveal the histology of the myocardium. Echocardiography was utilized to reveal cardiac function of mice. Flow cytometer analysis was used to reveal cell apoptosis. Luciferase reporter assay was applied for determining the binding capacity between molecules. We discovered that the level of miR-467a-5p was up-regulated in MI mice and in MCMs induced by H2O2 or hypoxia. Functionally, an elevation of left ventricular end-diastolic diameter and left ventricular end-systolic diameter, as well as a decrease of left ventricular ejection fraction and left ventricular fractional shortening were observed in MI mice. In addition, deficiency of miR-467a-5p improved MI in mice by increasing the contents of lactate dehydrogenase, creatine kinase and malondialdehyde and reducing the activity of superoxide dismutase in serum. Moreover, silencing of miR-467a-5p reversed hypoxia-induced apoptosis of MCMs. Mechanistically, zinc finger E-box binding homeobox 1 (ZEB1) was confirmed as the target of miR-467a-5p. Moreover, miR-467a-5p negatively regulated ZEB1 level in MI mice and MCMs. Finally, the promotive effect of miR-467a-5p inhibition on cell apoptosis was reversed by knockdown of ZEB1. All the experimental results demonstrate that miR-467a-5p aggravates MI by modulating ZEB1 expression in mice, which may provide a novel therapeutic strategy for MI.
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Chang J, Yan J, Li X, Liu N, Zheng R, Zhong Y. Update on the Mechanisms of Tubular Cell Injury in Diabetic Kidney Disease. Front Med (Lausanne) 2021; 8:661076. [PMID: 33859992 PMCID: PMC8042139 DOI: 10.3389/fmed.2021.661076] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 03/08/2021] [Indexed: 02/06/2023] Open
Abstract
Increasing evidence supports a role of proximal tubular (PT) injury in the progression of diabetic kidney disease (DKD), in patients with or without proteinuria. Research on the mechanisms of the PT injury in DKD could help us to identify potential new biomarkers and drug targets for DKD. A high glucose transport state and mismatched local hypoxia in the PT of diabetes patients may be the initiating factors causing PT injury. Other mechanism such as mitochondrial dysfunction, reactive oxygen species (ROS) overproduction, ER stress, and deficiency of autophagy interact with each other leading to more PT injury by forming a vicious circle. PT injury eventually leads to the development of tubulointerstitial inflammation and fibrosis in DKD. Many downstream signaling pathways have been demonstrated to mediate these diseased processes. This review focuses mostly on the novel mechanisms of proximal renal tubular injury in DKD and we believe such review could help us to better understand the pathogenesis of DKD and identify potential new therapies for this disease.
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Affiliation(s)
- Jingsheng Chang
- Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiayi Yan
- Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xueling Li
- Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ni Liu
- Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Rong Zheng
- Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yifei Zhong
- Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Gu YY, Lu FH, Huang XR, Zhang L, Mao W, Yu XQ, Liu XS, Lan HY. Non-Coding RNAs as Biomarkers and Therapeutic Targets for Diabetic Kidney Disease. Front Pharmacol 2021; 11:583528. [PMID: 33574750 PMCID: PMC7870688 DOI: 10.3389/fphar.2020.583528] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 12/14/2020] [Indexed: 12/20/2022] Open
Abstract
Diabetic kidney disease (DKD) is the most common diabetic complication and is a leading cause of end-stage kidney disease. Increasing evidence shows that DKD is regulated not only by many classical signaling pathways but also by epigenetic mechanisms involving chromatin histone modifications, DNA methylation, and non-coding RNA (ncRNAs). In this review, we focus on our current understanding of the role and mechanisms of ncRNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in the pathogenesis of DKD. Of them, the regulatory role of TGF-β/Smad3-dependent miRNAs and lncRNAs in DKD is highlighted. Importantly, miRNAs and lncRNAs as biomarkers and therapeutic targets for DKD are also described, and the perspective of ncRNAs as a novel therapeutic approach for combating diabetic nephropathy is also discussed.
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Affiliation(s)
- Yue-Yu Gu
- Department of Nephrology and State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Fu-Hua Lu
- Department of Nephrology and State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiao-Ru Huang
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
- Guangdong-Hong Kong Joint Laboratory for Immunological and Genetic Kidney Diseases, Guangdong Academy of Medical Sciences, Guangdong Provincial People’s Hospital, Guangzhou, China
- Guangdong-Hong Kong Joint Laboratory for Immunological and Genetic Kidney Diseases, The Chinese University of Hong Kong, Hong Kong, China
| | - Lei Zhang
- Department of Nephrology and State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wei Mao
- Department of Nephrology and State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xue-Qing Yu
- Guangdong-Hong Kong Joint Laboratory for Immunological and Genetic Kidney Diseases, Guangdong Academy of Medical Sciences, Guangdong Provincial People’s Hospital, Guangzhou, China
| | - Xu-Sheng Liu
- Department of Nephrology and State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hui-Yao Lan
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
- Guangdong-Hong Kong Joint Laboratory for Immunological and Genetic Kidney Diseases, Guangdong Academy of Medical Sciences, Guangdong Provincial People’s Hospital, Guangzhou, China
- Guangdong-Hong Kong Joint Laboratory for Immunological and Genetic Kidney Diseases, The Chinese University of Hong Kong, Hong Kong, China
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12
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Li M, Guo Q, Cai H, Wang H, Ma Z, Zhang X. miR-218 regulates diabetic nephropathy via targeting IKK-β and modulating NK-κB-mediated inflammation. J Cell Physiol 2020; 235:3362-3371. [PMID: 31549412 DOI: 10.1002/jcp.29224] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 09/03/2019] [Indexed: 01/03/2023]
Abstract
Diabetic nephropathy (DN) is a common clinically relevant complication of diabetes that is associated with damage to the capillaries, yet the etiology of this condition remains unclear. Nuclear factor-kappa B (NF-κB) activation is known to be associated with DN-related inflammation and disease progression. Recent work indicated that microRNAs are diagnostic biomarkers of DN progression associated with inflammation in the progression of DN. miR-218 is known to play key regulatory roles in certain cancers in humans, while its influence on DN pathology remains uncertain. The present study, therefore, sought to assess how miR-218 influences the progression of disease in both a rat streptozotocin-induced model of DN and as well as an in vitro model system in which mouse podocytes were stimulated with high glucose levels. We found miR-218 to be markedly downregulated in both model systems relative to appropriate controls, and this downregulation was associated with IKK-β upregulation. In DN rat model, overexpressing miR-218 was sufficient to reduce renal injury. We further determined that podocyte proliferation was markedly impaired by glucose treatment, leading to the apoptotic death of these cells, and miR-218 mimics were able to reduce these phenotypes. Overexpressing miR-218 also significantly dampened inflammatory responses in this model system, as evidenced by reduced tumor necrosis factor-α, interleukin-6 (IL-6), IL-1β, and MCP-1 levels. We then confirmed that miR-218 targeting the messenger RNA encoding IKK-β using a dual-luciferase reporter assay. Together, our results provide clear evidence that miR-218 regulate NF-κB-mediated inflammation, which is central to DN progression.
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Affiliation(s)
- Mo Li
- Department of Endocrinology, Second Hospital of Jilin University, Changchun, China
| | - Qiushi Guo
- Department of Pharmacy, The Second Part of First Hospital, Jilin University, Changchun, China
| | - Hanqing Cai
- Department of Endocrinology, Second Hospital of Jilin University, Changchun, China
| | - Haiyang Wang
- Department of Endocrinology, Second Hospital of Jilin University, Changchun, China
| | - Zhiming Ma
- Department of Gastrointestinal Nutrition and Hernia Surgery, Second Hospital of Jilin University, Changchun, China
| | - Xuan Zhang
- Department of Nephropathy, Second Hospital of Jilin University, Changchun, China
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13
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Feng YL, Chen DQ, Vaziri ND, Guo Y, Zhao YY. Small molecule inhibitors of epithelial-mesenchymal transition for the treatment of cancer and fibrosis. Med Res Rev 2020; 40:54-78. [PMID: 31131921 DOI: 10.1002/med.21596] [Citation(s) in RCA: 102] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 03/20/2019] [Accepted: 04/26/2019] [Indexed: 02/07/2023]
Abstract
Tissue fibrosis and cancer both lead to high morbidity and mortality worldwide; thus, effective therapeutic strategies are urgently needed. Because drug resistance has been widely reported in fibrotic tissue and cancer, developing a strategy to discover novel targets for targeted drug intervention is necessary for the effective treatment of fibrosis and cancer. Although many factors lead to fibrosis and cancer, pathophysiological analysis has demonstrated that tissue fibrosis and cancer share a common process of epithelial-mesenchymal transition (EMT). EMT is associated with many mediators, including transcription factors (Snail, zinc-finger E-box-binding protein and signal transducer and activator of transcription 3), signaling pathways (transforming growth factor-β1, RAC-α serine/threonine-protein kinase, Wnt, nuclear factor-kappa B, peroxisome proliferator-activated receptor, Notch, and RAS), RNA-binding proteins (ESRP1 and ESRP2) and microRNAs. Therefore, drugs targeting EMT may be a promising therapy against both fibrosis and tumors. A large number of compounds that are synthesized or derived from natural products and their derivatives suppress the EMT by targeting these mediators in fibrosis and cancer. By targeting EMT, these compounds exhibited anticancer effects in multiple cancer types, and some of them also showed antifibrotic effects. Therefore, drugs targeting EMT not only have both antifibrotic and anticancer effects but also exert effective therapeutic effects on multiorgan fibrosis and cancer, which provides effective therapy against fibrosis and cancer. Taken together, the results highlighted in this review provide new concepts for discovering new antifibrotic and antitumor drugs.
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Affiliation(s)
- Ya-Long Feng
- School of Pharmacy, Faculty of Life Science & Medicine, Northwest University, Xi'an, Shaanxi, China
| | - Dan-Qian Chen
- School of Pharmacy, Faculty of Life Science & Medicine, Northwest University, Xi'an, Shaanxi, China
| | - Nosratola D Vaziri
- Department of Medicine, University of California Irvine, Irvine, California
| | - Yan Guo
- School of Pharmacy, Faculty of Life Science & Medicine, Northwest University, Xi'an, Shaanxi, China
- Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico
| | - Ying-Yong Zhao
- School of Pharmacy, Faculty of Life Science & Medicine, Northwest University, Xi'an, Shaanxi, China
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14
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Jiang ZH, Tang YZ, Song HN, Yang M, Li B, Ni CL. miRNA‑342 suppresses renal interstitial fibrosis in diabetic nephropathy by targeting SOX6. Int J Mol Med 2019; 45:45-52. [PMID: 31746345 PMCID: PMC6889927 DOI: 10.3892/ijmm.2019.4388] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 09/17/2019] [Indexed: 12/20/2022] Open
Abstract
Diabetic kidney disease (DKD) is one of the major microvascular complications in patients with type 1 and/or type 2 diabetes, the first cause of end-stage renal disease (ESRD) in several countries and regions. However, the pathogenesis of DKD and the mechanisms through which it leads to ESRD remain unknown. Thus, in this study, we aimed to elucidate some of these mechanisms. The expression of microRNA (miRNA or miR)-342-3p and SRY-box 6 (SOX6) in the renal tissues of mice with DKD and mouse renal mesangial cells (MCs) was determined by RT-qPCR and western blot analysis. The diabetic kidney environment was established using high-glucose medium. SOX6 was verified as a target gene of miR-342-3p by dual-luciferase activity assay. In addition, western blot analysis was employed to determine the changes in the levels of several biomarkers of fibrosis [transforming growth factor (TGF)-β1, fibronectin (FN), collagen IV (referred to as C-IV) and phosphatase and tensin homolog (PTEN)]. Compared with THE control mice, the expression of miR-342-3p in the kidney tissues of mice with DKD was down-regulated, whereas that of SOX6 was upregulated. The same phenomenon was observed in the MCs cultured in high-glucose medium. Subsequently, miR-342-3p inhibited SOX6 expression, promoted cell proliferation and inhibited the apoptosis of MCs. Moreover, the overexpression of miR-342-3p suppressed high glucose-induced renal interstitial fibrosis. In addition, it was found that miR-342-3p inhibited SOX6 expression by binding to the 3′-UTR of SOX6. On the whole, the findings of this study demonstrate that miR-342-3p suppresses the progression of DKD by inducing the degradation of SOX6. Thus, the miR-342-3p/SOX6 axis may serve as a novel therapeutic target in the treatment of DKD.
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Affiliation(s)
- Zhen-Huan Jiang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien‑I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin 300134, P.R. China
| | - Yun-Zhao Tang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien‑I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin 300134, P.R. China
| | - Hong-Na Song
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien‑I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin 300134, P.R. China
| | - Min Yang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien‑I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin 300134, P.R. China
| | - Bin Li
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien‑I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin 300134, P.R. China
| | - Chang-Lin Ni
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien‑I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin 300134, P.R. China
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15
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Ji T, Su SL, Zhu Y, Guo JM, Qian DW, Tang YP, Duan JA. The mechanism of mulberry leaves against renal tubular interstitial fibrosis through ERK1/2 signaling pathway was predicted by network pharmacology and validated in human tubular epithelial cells. Phytother Res 2019; 33:2044-2055. [PMID: 31209937 DOI: 10.1002/ptr.6390] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 02/18/2019] [Accepted: 04/23/2019] [Indexed: 12/24/2022]
Abstract
Mulberry leaf was reported that it has antidiabetic activity, although the mechanisms underlying the function have not been fully elucidated. In the present study, the results of network pharmacology suggested that mulberry leaves could regulate key biological process in development of diabetes, and the process implicates multiple signaling pathways, such as JAK-STAT, MAPK, VEGF, PPAR, and Wnt. Then, the research in vitro indicated that mulberry leaves remarkably ameliorated high glucose-induced epithelial to mesenchymal transition, which was characterized with significant reduction of intracellular reactive oxygen species (ROS) levels as well as downregulation of NADPH oxidase subunits NOX1, NOX2, and NOX4, and it was found to be connected with the ERK1/2 signaling pathway in human tubular epithelial cells (HK-2). Moreover, the results of bioinformatics and the dual luciferase report showed that ZEB1 might be a target gene of miR-302a; decreased miR-302a and increased ZEB1 expressions could significantly promote epithelial to mesenchymal transition. However, mulberry leaves could reverse these modulations. Our results demonstrated that network pharmacology could provide a guidance role for traditional Chinese medicine research, and mulberry leaves could be of benefit in preventing high glucose-induced EMT in HK-2 cells, which proved that it was related to the upregulation of miR-302a by targeting ZEB1 and the inhibition of NADPH oxidase/ROS/ERK1/2 pathway.
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Affiliation(s)
- Tao Ji
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing, China.,Institute of traditional Chinese medicine, Zhejiang pharmaceutical college, Ningbo, 310053, China
| | - Shu-Lan Su
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yue Zhu
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jian-Ming Guo
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing, China
| | - Da-Wei Qian
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yu-Ping Tang
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jin-Ao Duan
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing, China
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16
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Dewanjee S, Bhattacharjee N. MicroRNA: A new generation therapeutic target in diabetic nephropathy. Biochem Pharmacol 2018; 155:32-47. [DOI: 10.1016/j.bcp.2018.06.017] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Accepted: 06/20/2018] [Indexed: 12/11/2022]
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17
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Yao T, Zha D, Gao P, Shui H, Wu X. MiR-874 alleviates renal injury and inflammatory response in diabetic nephropathy through targeting toll-like receptor-4. J Cell Physiol 2018; 234:871-879. [PMID: 30171701 DOI: 10.1002/jcp.26908] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 06/13/2018] [Indexed: 01/01/2023]
Abstract
Diabetic nephropathy (DN) is a kind of diabetic complication with capillary damage, and its pathogenesis remains obscure. Recently, microRNAs have been identified as diagnostic biomarkers in various diseases including DN. Toll-like receptor 4 (TLR4) contributes to inflammation, and it has been implicated in diabetes pathophysiology. This study was designed to investigate the role of miR-874 and TLR4 in a streptozotocin (STZ)-induced DN rat model and glucose-induced mouse podocyte model. In the current study, we reported that miR-874 was markedly downregulated in DN rats and glucose-induced mouse podocytes compared with the corresponding control groups with the activation of TLR4. In addition, we observed that overexpression of miR-874 was able to alleviate renal injury in DN rats. The cell counting kit (CCK-8) assay and 5-Ethynyl-2'-deoxyuridine (EdU) assay demonstrated that glucose simulation significantly inhibited podocyte proliferation and induced cell apoptosis, which can be reversed by miR-874 mimics significantly. Notably, miR-874 overexpression dramatically attenuated the inflammatory response, indicated by the decreased levels of interleukin-6, L-1β, and tumor necrosis factor α (TNF-α). Finally, the binding correlation between miR-874 and TLR4 was confirmed by carrying out dual-luciferase reporter assay in our study. It was found that overexpression of miR-874 depressed TLR4 levels in podocytes. These findings implied for the first time that the overexpression of miR-874 repressed glucose-triggered podocyte injury through targeting TLR4 and suggested that miR-874/TLR4 axis might represent a pathological mechanism of DN.
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Affiliation(s)
- Tao Yao
- Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Dongqing Zha
- Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Ping Gao
- Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Hua Shui
- Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Xiaoyan Wu
- Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China
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18
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Schulz MC, Schumann L, Rottkord U, Humpf HU, Gekle M, Schwerdt G. Synergistic action of the nephrotoxic mycotoxins ochratoxin A and citrinin at nanomolar concentrations in human proximal tubule-derived cells. Toxicol Lett 2018; 291:149-157. [DOI: 10.1016/j.toxlet.2018.04.014] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Revised: 04/12/2018] [Accepted: 04/14/2018] [Indexed: 12/31/2022]
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19
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Functional Role of Non-Coding RNAs during Epithelial-To-Mesenchymal Transition. Noncoding RNA 2018; 4:ncrna4020014. [PMID: 29843425 PMCID: PMC6027143 DOI: 10.3390/ncrna4020014] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 05/22/2018] [Accepted: 05/23/2018] [Indexed: 01/17/2023] Open
Abstract
Epithelial-to-mesenchymal transition (EMT) is a key biological process involved in a multitude of developmental and pathological events. It is characterized by the progressive loss of cell-to-cell contacts and actin cytoskeletal rearrangements, leading to filopodia formation and the progressive up-regulation of a mesenchymal gene expression pattern enabling cell migration. Epithelial-to-mesenchymal transition is already observed in early embryonic stages such as gastrulation, when the epiblast undergoes an EMT process and therefore leads to the formation of the third embryonic layer, the mesoderm. Epithelial-to-mesenchymal transition is pivotal in multiple embryonic processes, such as for example during cardiovascular system development, as valve primordia are formed and the cardiac jelly is progressively invaded by endocardium-derived mesenchyme or as the external cardiac cell layer is established, i.e., the epicardium and cells detached migrate into the embryonic myocardial to form the cardiac fibrous skeleton and the coronary vasculature. Strikingly, the most important biological event in which EMT is pivotal is cancer development and metastasis. Over the last years, understanding of the transcriptional regulatory networks involved in EMT has greatly advanced. Several transcriptional factors such as Snail, Slug, Twist, Zeb1 and Zeb2 have been reported to play fundamental roles in EMT, leading in most cases to transcriptional repression of cell⁻cell interacting proteins such as ZO-1 and cadherins and activation of cytoskeletal markers such as vimentin. In recent years, a fundamental role for non-coding RNAs, particularly microRNAs and more recently long non-coding RNAs, has been identified in normal tissue development and homeostasis as well as in several oncogenic processes. In this study, we will provide a state-of-the-art review of the functional roles of non-coding RNAs, particularly microRNAs, in epithelial-to-mesenchymal transition in both developmental and pathological EMT.
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