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Gembillo G, Spadaro G, Santoro D. Link between obstructive uropathy and acute kidney injury. World J Nephrol 2025; 14:99120. [DOI: 10.5527/wjn.v14.i1.99120] [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: 07/14/2024] [Revised: 10/10/2024] [Accepted: 11/19/2024] [Indexed: 01/20/2025] Open
Abstract
Obstructive uropathy represents a major risk of acute kidney injury. From an epidemiological point of view, it is responsible for 5% to 10% of cases of acute renal failure and 4% of cases of end-stage kidney disease. Although obstructive uropathy is a recognized disease, there is a significant lack of detailed research on this topic from both a nephrological and urological perspective. The majority of published research focuses on the pathophysiology of the topic and neglects a comprehensive analysis of diagnostic and treatment approaches supported by current data. In this context, it is crucial to assess the overall hemodynamic status, especially in the presence of urosepsis. Once clinical stability is assured, it is important to focus on symptom management, usually by controlling pain. Ultimately, it is crucial to decide immediately whether the patient should receive a prompt urinary diversion. Urinary diversion is an essential part of the treatment of obstructive uropathy and should be initiated promptly and without unnecessary delay once the diagnosis has been confirmed. Functional recovery of the obstructed kidney after decompression of the urinary tract depends on the degree of obstruction, the duration of the obstruction and the presence of a concomitant urinary tract infection. The timing and proper treatment of this condition determines the recovery of kidney function after an obstruction and prevents the development of chronic kidney disease. In this editorial, we emphasized the pathophysiological role and clinical significance of obstructive uropathy in the context of acute kidney injury.
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Affiliation(s)
- Guido Gembillo
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina 98125, Italy
| | - Giuseppe Spadaro
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina 98125, Italy
| | - Domenico Santoro
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina 98125, Italy
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Kuo HL, Chuang HL, Chen CM, Chen YY, Chen YS, Lin SC, Weng PY, Liu TC, Wang PY, Huang CF, Guan SS, Liu SH, Yang SF, Wu CT. Wogonin ameliorates ER stress-associated inflammatory response, apoptotic death and renal fibrosis in a unilateral ureteral obstruction mouse model. Eur J Pharmacol 2024; 977:176676. [PMID: 38815787 DOI: 10.1016/j.ejphar.2024.176676] [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: 02/16/2024] [Revised: 04/27/2024] [Accepted: 05/27/2024] [Indexed: 06/01/2024]
Abstract
Wogonin, a vital bioactive compound extracted from the medicinal plant, Scutellaria baicalensis, has been wildly used for its potential in mitigating the progression of chronic diseases. Chronic kidney disease (CKD) represents a significant global health challenge due to its high prevalence, morbidity and mortality rates, and associated complications. This study aimed to assess the potential of wogonin in attenuating renal fibrosis and to elucidate the underlying molecular mechanisms using a unilateral ureteral obstruction (UUO) mouse model as a CKD mimic. Male mice, 8 weeks old, underwent orally administrated of either 50 mg/kg/day of wogonin or positive control of 5 mg/kg/day candesartan following UUO surgery. NRK52E cells were exposed to tumor growth factors-beta (TGF-β) to evaluate the anti-fibrotic effects of wogonin. The results demonstrated that wogonin treatment effectively attenuated TGF-β-induced fibrosis markers in NRK-52E cells. Additionally, administration of wogonin significantly improved histopathological alterations and downregulated the expression of pro-fibrotic factors (Fibronectin, α-smooth muscle actin, Collagen IV, E-cadherin, and TGF-β), oxidative stress markers (Catalase, superoxide dismutase 2, NADPH oxidase 4, and thioredoxin reductase 1), inflammatory molecules (Cyclooxygenase-2 and TNF-α), and the infiltration of neutrophils and macrophages in UUO mice. Furthermore, wogonin treatment mitigated endoplasmic reticulum (ER) stress-associated molecular markers (GRP78, GRP94, ATF4, CHOP, and the caspase cascade) and suppressed apoptosis. The findings indicate that wogonin treatment ameliorates key fibrotic aspects of CKD by attenuating ER stress-related apoptosis, inflammation, and oxidative stress, suggesting its potential as a future therapeutic target.
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Affiliation(s)
- Huey-Liang Kuo
- School of Medicine, China Medical University, Taichung, 40402, Taiwan; Division of Nephrology, Department of Internal Medicine, China Medical University Hospital, Taichung, 40402, Taiwan; Clinical Nutrition, China Medical University Hospital, Taichung, 40402, Taiwan.
| | - Haw-Ling Chuang
- Department of Emergency, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, 427, Taiwan.
| | - Chang-Mu Chen
- Division of Neurosurgery, Department of Surgery, College of Medicine and Hospital, National Taiwan University, Taipei 10051, Taiwan.
| | - Yu-Ya Chen
- Department of Nutrition, China Medical University, Taichung, Taiwan, 40402, ROC.
| | - Yu-Syuan Chen
- Department of Nutrition, China Medical University, Taichung, Taiwan, 40402, ROC.
| | - Ssu-Chia Lin
- Department of Nutrition, China Medical University, Taichung, Taiwan, 40402, ROC.
| | - Pei-Yu Weng
- Department of Nutrition, China Medical University, Taichung, Taiwan, 40402, ROC.
| | - Ting-Chun Liu
- Department of Nutrition, China Medical University, Taichung, Taiwan, 40402, ROC.
| | - Pei-Yun Wang
- Department of Nutrition, China Medical University, Taichung, Taiwan, 40402, ROC.
| | - Chun-Fa Huang
- School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan; Department of Nursing, College of Medical and Health Science, Asia University, Taichung, 413, Taiwan.
| | - Siao-Syun Guan
- Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan, 32546, Taiwan.
| | - Shing-Hwa Liu
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan.
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, 40201, Taiwan; Department of Medical Research, Chung Shan Medical University Hospital, Taichung, 40201, Taiwan.
| | - Cheng-Tien Wu
- Department of Nutrition, China Medical University, Taichung, Taiwan, 40402, ROC; Master Program of Food and Drug Safety, China Medical University, Taichung, 406040, Taiwan.
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Cui L, Li X, Chen Z, Liu Z, Zhang Y, Han Z, Liu S, Li H. Integrative RNA-seq and ChIP-seq analysis unveils metabolic regulation as a conserved antiviral mechanism of chicken p53. Microbiol Spectr 2024; 12:e0030924. [PMID: 38888361 PMCID: PMC11302347 DOI: 10.1128/spectrum.00309-24] [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: 02/02/2024] [Accepted: 05/02/2024] [Indexed: 06/20/2024] Open
Abstract
The tumor suppressor p53, primarily functioning as a transcription factor, has exhibited antiviral capabilities against various viruses in chickens, including infectious bursal disease virus (IBDV), avian leukosis virus subgroup J (ALV-J), and avian infectious laryngotracheitis virus (ILTV). Nevertheless, the existence of a universal antiviral mechanism employed by chicken p53 (chp53) against these viruses remains uncertain. This study conducted a comprehensive comparison of molecular networks involved in chp53's antiviral function against IBDV, ALV-J, and ILTV. This was achieved through an integrated analysis of ChIP-seq data, examining chp53's genome-wide chromatin occupancy, and RNA-seq data from chicken cells infected with these viruses. The consistent observation of chp53 target gene enrichment in metabolic pathways, confirmed via ChIP-qPCR, suggests a ubiquitous regulation of host cellular metabolism by chp53 across different viruses. Further genome binding motif conservation analysis and transcriptional co-factor prediction suggest conserved transcriptional regulation mechanism by which chp53 regulates host cellular metabolism during viral infection. These findings offer novel insights into the antiviral role of chp53 and propose that targeting the virus-host metabolic interaction through regulating p53 could serve as a universal strategy for antiviral therapies in chickens.IMPORTANCEThe current study conducted a comprehensive analysis, comparing molecular networks underlying chp53's antiviral role against infectious bursal disease virus (IBDV), avian leukosis virus subgroup J (ALV-J), and avian infectious laryngotracheitis virus (ILTV). This was achieved through a combined assessment of ChIP-seq and RNA-seq data obtained from infected chicken cells. Notably, enrichment of chp53 target genes in metabolic pathways was consistently observed across viral infections, indicating a universal role of chp53 in regulating cellular metabolism during diverse viral infections. These findings offer novel insights into the antiviral capabilities of chicken p53, laying a foundation for the potential development of broad-spectrum antiviral therapies in chickens.
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Affiliation(s)
- Lu Cui
- Division of Avian Infectious Diseases, State Key Laboratory for Animal Disease Control and Prevention, National Poultry Laboratory Animal Resource Center, Harbin Veterinary Research Institute, the Chinese Academy of Agricultural Sciences, Harbin, China
| | - Xuefeng Li
- Division of Avian Infectious Diseases, State Key Laboratory for Animal Disease Control and Prevention, National Poultry Laboratory Animal Resource Center, Harbin Veterinary Research Institute, the Chinese Academy of Agricultural Sciences, Harbin, China
| | - Zhijie Chen
- Division of Avian Infectious Diseases, State Key Laboratory for Animal Disease Control and Prevention, National Poultry Laboratory Animal Resource Center, Harbin Veterinary Research Institute, the Chinese Academy of Agricultural Sciences, Harbin, China
| | - Zheyi Liu
- Division of Avian Infectious Diseases, State Key Laboratory for Animal Disease Control and Prevention, National Poultry Laboratory Animal Resource Center, Harbin Veterinary Research Institute, the Chinese Academy of Agricultural Sciences, Harbin, China
| | - Yu Zhang
- Division of Avian Infectious Diseases, State Key Laboratory for Animal Disease Control and Prevention, National Poultry Laboratory Animal Resource Center, Harbin Veterinary Research Institute, the Chinese Academy of Agricultural Sciences, Harbin, China
| | - Zongxi Han
- Division of Avian Infectious Diseases, State Key Laboratory for Animal Disease Control and Prevention, National Poultry Laboratory Animal Resource Center, Harbin Veterinary Research Institute, the Chinese Academy of Agricultural Sciences, Harbin, China
| | - Shengwang Liu
- Division of Avian Infectious Diseases, State Key Laboratory for Animal Disease Control and Prevention, National Poultry Laboratory Animal Resource Center, Harbin Veterinary Research Institute, the Chinese Academy of Agricultural Sciences, Harbin, China
| | - Hai Li
- Division of Avian Infectious Diseases, State Key Laboratory for Animal Disease Control and Prevention, National Poultry Laboratory Animal Resource Center, Harbin Veterinary Research Institute, the Chinese Academy of Agricultural Sciences, Harbin, China
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Czekay RP, Higgins CE, Aydin HB, Samarakoon R, Subasi NB, Higgins SP, Lee H, Higgins PJ. SERPINE1: Role in Cholangiocarcinoma Progression and a Therapeutic Target in the Desmoplastic Microenvironment. Cells 2024; 13:796. [PMID: 38786020 PMCID: PMC11119900 DOI: 10.3390/cells13100796] [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: 04/04/2024] [Revised: 05/03/2024] [Accepted: 05/03/2024] [Indexed: 05/25/2024] Open
Abstract
A heterogenous population of inflammatory elements, other immune and nonimmune cells and cancer-associated fibroblasts (CAFs) are evident in solid malignancies where they coexist with the growing tumor mass. In highly desmoplastic malignancies, CAFs are the prominent mesenchymal cell type in the tumor microenvironment (TME), where their presence and abundance signal a poor prognosis. CAFs play a major role in the progression of various cancers by remodeling the supporting stroma into a dense, fibrotic matrix while secreting factors that promote the maintenance of cancer stem-like characteristics, tumor cell survival, aggressive growth and metastasis and reduced sensitivity to chemotherapeutics. Tumors with high stromal fibrotic signatures are more likely to be associated with drug resistance and eventual relapse. Identifying the molecular underpinnings for such multidirectional crosstalk among the various normal and neoplastic cell types in the TME may provide new targets and novel opportunities for therapeutic intervention. This review highlights recent concepts regarding the complexity of CAF biology in cholangiocarcinoma, a highly desmoplastic cancer. The discussion focuses on CAF heterogeneity, functionality in drug resistance, contributions to a progressively fibrotic tumor stroma, the involved signaling pathways and the participating genes.
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Affiliation(s)
- Ralf-Peter Czekay
- Department of Regenerative & Cancer Cell Biology, Albany Medical College, Albany, NY 12208, USA; (R.-P.C.); (C.E.H.); (R.S.); (S.P.H.)
| | - Craig E. Higgins
- Department of Regenerative & Cancer Cell Biology, Albany Medical College, Albany, NY 12208, USA; (R.-P.C.); (C.E.H.); (R.S.); (S.P.H.)
| | - Hasan Basri Aydin
- Department of Pathology & Laboratory Medicine, Albany Medical College, Albany, NY 12208, USA; (H.B.A.); (N.B.S.); (H.L.)
| | - Rohan Samarakoon
- Department of Regenerative & Cancer Cell Biology, Albany Medical College, Albany, NY 12208, USA; (R.-P.C.); (C.E.H.); (R.S.); (S.P.H.)
| | - Nusret Bekir Subasi
- Department of Pathology & Laboratory Medicine, Albany Medical College, Albany, NY 12208, USA; (H.B.A.); (N.B.S.); (H.L.)
| | - Stephen P. Higgins
- Department of Regenerative & Cancer Cell Biology, Albany Medical College, Albany, NY 12208, USA; (R.-P.C.); (C.E.H.); (R.S.); (S.P.H.)
| | - Hwajeong Lee
- Department of Pathology & Laboratory Medicine, Albany Medical College, Albany, NY 12208, USA; (H.B.A.); (N.B.S.); (H.L.)
| | - Paul J. Higgins
- Department of Regenerative & Cancer Cell Biology, Albany Medical College, Albany, NY 12208, USA; (R.-P.C.); (C.E.H.); (R.S.); (S.P.H.)
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Yun QS, Bao YX, Jiang JB, Guo Q. Mechanisms of norcantharidin against renal tubulointerstitial fibrosis. Pharmacol Rep 2024; 76:263-272. [PMID: 38472637 DOI: 10.1007/s43440-024-00578-5] [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: 09/02/2023] [Revised: 02/15/2024] [Accepted: 02/16/2024] [Indexed: 03/14/2024]
Abstract
Renal tubulointerstitial fibrosis (RTIF) is a common feature and inevitable consequence of all progressive chronic kidney diseases, leading to end-stage renal failure regardless of the initial cause. Although research over the past few decades has greatly improved our understanding of the pathophysiology of RTIF, until now there has been no specific treatment available that can halt the progression of RTIF. Norcantharidin (NCTD) is a demethylated analogue of cantharidin, a natural compound isolated from 1500 species of medicinal insect, the blister beetle (Mylabris phalerata Pallas), traditionally used for medicinal purposes. Many studies have found that NCTD can attenuate RTIF and has the potential to be an anti-RTIF drug. This article reviews the recent progress of NCTD in the treatment of RTIF, with emphasis on the pharmacological mechanism of NCTD against RTIF.
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Affiliation(s)
- Qin-Su Yun
- Department of Pharmacy, The First People's Hospital of Changzhou and the 3rd Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, Jiangsu, China
| | - Yu-Xin Bao
- Research Center for Medicine and Biology, Zunyi Medical University, 6 West Xuefu Road, Zunyi, 563000, Guizhou, China.
| | - Jie-Bing Jiang
- Department of Pharmacology, Naval Medical University, Shanghai, 200433, China
| | - Qian Guo
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, 881 Yonghe Road, Nantong, 226001 , Jiangsu, China.
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, 99 Shangda Road, Shanghai, 200444, China.
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Nørregaard R, Mutsaers HAM, Frøkiær J, Kwon TH. Obstructive nephropathy and molecular pathophysiology of renal interstitial fibrosis. Physiol Rev 2023; 103:2827-2872. [PMID: 37440209 PMCID: PMC10642920 DOI: 10.1152/physrev.00027.2022] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 07/05/2023] [Accepted: 07/09/2023] [Indexed: 07/14/2023] Open
Abstract
The kidneys play a key role in maintaining total body homeostasis. The complexity of this task is reflected in the unique architecture of the organ. Ureteral obstruction greatly affects renal physiology by altering hemodynamics, changing glomerular filtration and renal metabolism, and inducing architectural malformations of the kidney parenchyma, most importantly renal fibrosis. Persisting pathological changes lead to chronic kidney disease, which currently affects ∼10% of the global population and is one of the major causes of death worldwide. Studies on the consequences of ureteral obstruction date back to the 1800s. Even today, experimental unilateral ureteral obstruction (UUO) remains the standard model for tubulointerstitial fibrosis. However, the model has certain limitations when it comes to studying tubular injury and repair, as well as a limited potential for human translation. Nevertheless, ureteral obstruction has provided the scientific community with a wealth of knowledge on renal (patho)physiology. With the introduction of advanced omics techniques, the classical UUO model has remained relevant to this day and has been instrumental in understanding renal fibrosis at the molecular, genomic, and cellular levels. This review details key concepts and recent advances in the understanding of obstructive nephropathy, highlighting the pathophysiological hallmarks responsible for the functional and architectural changes induced by ureteral obstruction, with a special emphasis on renal fibrosis.
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Affiliation(s)
- Rikke Nørregaard
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | | | - Jørgen Frøkiær
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Tae-Hwan Kwon
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Taegu, Korea
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Overstreet JM, Gifford CC, Tang J, Higgins PJ, Samarakoon R. Emerging role of tumor suppressor p53 in acute and chronic kidney diseases. Cell Mol Life Sci 2022; 79:474. [PMID: 35941392 PMCID: PMC11072039 DOI: 10.1007/s00018-022-04505-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/20/2022] [Accepted: 07/21/2022] [Indexed: 02/06/2023]
Abstract
p53 is a major regulator of cell cycle arrest, apoptosis, and senescence. While involvement of p53 in tumorigenesis is well established, recent studies implicate p53 in the initiation and progression of several renal diseases, which is the focus of this review. Ischemic-, aristolochic acid (AA) -, diabetic-, HIV-associated-, obstructive- and podocyte-induced nephropathies are accompanied by activation and/or elevated expression of p53. Studies utilizing chemical or renal-specific inhibition of p53 in mice confirm the pathogenic role of this transcription factor in acute kidney injury and chronic kidney disease. TGF-β1, NOX, ATM/ATR kinases, Cyclin G, HIPK, MDM2 and certain micro-RNAs are important determinants of renal p53 function in response to trauma. AA, cisplatin or TGF-β1-mediated ROS generation via NOXs promotes p53 phosphorylation and subsequent tubular dysfunction. p53-SMAD3 transcriptional cooperation downstream of TGF-β1 orchestrates induction of fibrotic factors, extracellular matrix accumulation and pathogenic renal cell communication. TGF-β1-induced micro-RNAs (such as mir-192) could facilitate p53 activation, leading to renal hypertrophy and matrix expansion in response to diabetic insults while AA-mediated mir-192 induction regulates p53 dependent epithelial G2/M arrest. The widespread involvement of p53 in tubular maladaptive repair, interstitial fibrosis, and podocyte injury indicate that p53 clinical targeting may hold promise as a novel therapeutic strategy for halting progression of certain acute and chronic renal diseases, which affect hundreds of million people worldwide.
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Affiliation(s)
| | - Cody C Gifford
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY, 12208, USA
| | - Jiaqi Tang
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Paul J Higgins
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY, 12208, USA.
- Center for Cell Biology and Cancer Research, Albany Medical College, 47 New Scotland Avenue, Albany, NY, 12208, USA.
| | - Rohan Samarakoon
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY, 12208, USA.
- Center for Cell Biology and Cancer Research, Albany Medical College, 47 New Scotland Avenue, Albany, NY, 12208, USA.
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Wang W, Mu M, Zou Y, Li B, Cao H, Hu D, Tao X. Inflammation and fibrosis in the coal dust-exposed lung described by confocal Raman spectroscopy. PeerJ 2022; 10:e13632. [PMID: 35765591 PMCID: PMC9233900 DOI: 10.7717/peerj.13632] [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: 03/28/2022] [Accepted: 06/03/2022] [Indexed: 01/17/2023] Open
Abstract
Background Coal workers' pneumoconiosis (CWP) is an occupational disease that severely damages the life and health of miners. However, little is known about the molecular and cellular mechanisms changes associated with lung inflammation and fibrosis induced by coal dust. As a non-destructive technique for measuring biological tissue, confocal Raman spectroscopy provides accurate molecular fingerprints of label-free tissues and cells. Here, the progression of lung inflammation and fibrosis in a murine model of CWP was evaluated using confocal Raman spectroscopy. Methods A mouse model of CWP was constructed and biochemical analysis in lungs exposed to coal dust after 1 month (CWP-1M) and 3 months (CWP-3M) vs control tissues (NS) were used by confocal Raman spectroscopy. H&E, immunohistochemical and collagen staining were used to evaluate the histopathology alterations in the lung tissues. Results The CWP murine model was successfully constructed, and the mouse lung tissues showed progression of inflammation and fibrosis, accompanied by changes in NF-κB, p53, Bax, and Ki67. Meanwhile, significant differences in Raman bands were observed among the different groups, particularly changes at 1,248, 1,448, 1,572, and 746 cm-1. These changes were consistent with collagen, Ki67, and Bax levels in the CWP and NS groups. Conclusion Confocal Raman spectroscopy represented a novel approach to the identification of the biochemical changes in CWP lungs and provides potential biomarkers of inflammation and fibrosis.
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Affiliation(s)
- Wenyang Wang
- Key Laboratory of Industrial Dust Control and Occupational Health of the Ministry of Education, Anhui University of Science and Technology, Huainan, Anhui, China,Anhui Province Engineering Laboratory of Occupational Health and Safety, Huainan, Anhui, China,Anhui University of Science and Technology, Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Huainan, Anhui, China,Anhui University of Science and Technology, School of Medicine, Department of Medical Frontier Experimental Center, Huainan, Anhui, China
| | - Min Mu
- Key Laboratory of Industrial Dust Control and Occupational Health of the Ministry of Education, Anhui University of Science and Technology, Huainan, Anhui, China,Anhui Province Engineering Laboratory of Occupational Health and Safety, Huainan, Anhui, China,Anhui University of Science and Technology, Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Huainan, Anhui, China,Anhui University of Science and Technology, School of Medicine, Department of Medical Frontier Experimental Center, Huainan, Anhui, China
| | - Yuanjie Zou
- Key Laboratory of Industrial Dust Control and Occupational Health of the Ministry of Education, Anhui University of Science and Technology, Huainan, Anhui, China,Anhui Province Engineering Laboratory of Occupational Health and Safety, Huainan, Anhui, China,Anhui University of Science and Technology, School of Medicine, Department of Medical Frontier Experimental Center, Huainan, Anhui, China
| | - Bing Li
- Key Laboratory of Industrial Dust Control and Occupational Health of the Ministry of Education, Anhui University of Science and Technology, Huainan, Anhui, China,Anhui Province Engineering Laboratory of Occupational Health and Safety, Huainan, Anhui, China,Anhui University of Science and Technology, School of Medicine, Department of Medical Frontier Experimental Center, Huainan, Anhui, China
| | - Hangbing Cao
- Key Laboratory of Industrial Dust Control and Occupational Health of the Ministry of Education, Anhui University of Science and Technology, Huainan, Anhui, China,Anhui Province Engineering Laboratory of Occupational Health and Safety, Huainan, Anhui, China,Anhui University of Science and Technology, School of Medicine, Department of Medical Frontier Experimental Center, Huainan, Anhui, China
| | - Dong Hu
- Key Laboratory of Industrial Dust Control and Occupational Health of the Ministry of Education, Anhui University of Science and Technology, Huainan, Anhui, China,Anhui Province Engineering Laboratory of Occupational Health and Safety, Huainan, Anhui, China,Anhui University of Science and Technology, Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Huainan, Anhui, China,Anhui University of Science and Technology, School of Medicine, Department of Medical Frontier Experimental Center, Huainan, Anhui, China
| | - Xinrong Tao
- Key Laboratory of Industrial Dust Control and Occupational Health of the Ministry of Education, Anhui University of Science and Technology, Huainan, Anhui, China,Anhui Province Engineering Laboratory of Occupational Health and Safety, Huainan, Anhui, China,Anhui University of Science and Technology, Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Huainan, Anhui, China,Anhui University of Science and Technology, School of Medicine, Department of Medical Frontier Experimental Center, Huainan, Anhui, China
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Cancer-Associated Fibroblasts: Mechanisms of Tumor Progression and Novel Therapeutic Targets. Cancers (Basel) 2022; 14:cancers14051231. [PMID: 35267539 PMCID: PMC8909913 DOI: 10.3390/cancers14051231] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 02/17/2022] [Accepted: 02/24/2022] [Indexed: 12/14/2022] Open
Abstract
Simple Summary The tumor microenvironment plays an important role in determining the biological behavior of several of the more aggressive malignancies. Among the various cell types evident in the tumor “field”, cancer-associated fibroblasts (CAFs) are a heterogenous collection of activated fibroblasts secreting a wide repertoire of factors that regulate tumor development and progression, inflammation, drug resistance, metastasis and recurrence. Insensitivity to chemotherapeutics and metastatic spread are the major contributors to cancer patient mortality. This review discusses the complex interactions between CAFs and the various populations of normal and neoplastic cells that interact within the dynamic confines of the tumor microenvironment with a focus on the involved pathways and genes. Abstract Cancer-associated fibroblasts (CAFs) are a heterogenous population of stromal cells found in solid malignancies that coexist with the growing tumor mass and other immune/nonimmune cellular elements. In certain neoplasms (e.g., desmoplastic tumors), CAFs are the prominent mesenchymal cell type in the tumor microenvironment, where their presence and abundance signal a poor prognosis in multiple cancers. CAFs play a major role in the progression of various malignancies by remodeling the supporting stromal matrix into a dense, fibrotic structure while secreting factors that lead to the acquisition of cancer stem-like characteristics and promoting tumor cell survival, reduced sensitivity to chemotherapeutics, aggressive growth and metastasis. Tumors with high stromal fibrotic signatures are more likely to be associated with drug resistance and eventual relapse. Clarifying the molecular basis for such multidirectional crosstalk among the various normal and neoplastic cell types present in the tumor microenvironment may yield novel targets and new opportunities for therapeutic intervention. This review highlights the most recent concepts regarding the complexity of CAF biology including CAF heterogeneity, functionality in drug resistance, contribution to a progressively fibrotic tumor stroma, the involved signaling pathways and the participating genes.
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Li H, Duann P, Li Z, Zhou X, Ma J, Rovin BH, Lin PH. The cell membrane repair protein MG53 modulates transcription factor NF-κB signaling to control kidney fibrosis. Kidney Int 2022; 101:119-130. [PMID: 34757120 PMCID: PMC8741748 DOI: 10.1016/j.kint.2021.09.027] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 08/21/2021] [Accepted: 09/16/2021] [Indexed: 01/03/2023]
Abstract
Kidney fibrosis is associated with the progression of acute kidney injury to chronic kidney disease. MG53, a cell membrane repair protein, has been shown to protect against injury to kidney epithelial cells and acute kidney injury. Here, we evaluated the role of MG53 in modulation of kidney fibrosis in aging mice and in mice with unilateral ureteral obstruction (UUO) a known model of progressive kidney fibrosis. Mice with ablation of MG53 developed more interstitial fibrosis with age than MG53-intact mice of the same age. Similarly, in the absence of MG53, kidney fibrosis was exaggerated compared to mice with intact MG53 in the obstructed kidney compared to the contralateral unobstructed kidney or the kidneys of sham operated mice. The ureteral obstructed kidneys from MG53 deficient mice also showed significantly more inflammation than ureteral obstructed kidneys from MG53 intact mice. In vitro experiments demonstrated that MG53 could enter the nuclei of proximal tubular epithelial cells and directly interact with the p65 component of transcription factor NF-κB, providing a possible explanation of enhanced inflammation in the absence of MG53. To test this, enhanced MG53 expression through engineered cells or direct recombinant protein delivery was given to mice subject to UUO. This reduced NF-κB activation and inflammation and attenuated kidney fibrosis. Thus, MG53 may have a therapeutic role in treating chronic kidney inflammation and thereby provide protection against fibrosis that leads to the chronic kidney disease phenotype.
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Affiliation(s)
- Haichang Li
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210
| | - Pu Duann
- Research and Development, Salem Veteran Affairs Medical Center, Salem, VA 24153, USA
| | - Zhongguang Li
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210
| | - Xinyu Zhou
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210
| | - Jianjie Ma
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210
| | - Brad H. Rovin
- Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA,Correspondence: Pei-Hui Lin, Ph.D., Tel. (614) 292-2802, ; Brad H. Rovin, M.D., Tel. (614) 293-4997,
| | - Pei-Hui Lin
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210,Correspondence: Pei-Hui Lin, Ph.D., Tel. (614) 292-2802, ; Brad H. Rovin, M.D., Tel. (614) 293-4997,
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Gart E, van Duyvenvoorde W, Toet K, Caspers MPM, Verschuren L, Nielsen MJ, Leeming DJ, Souto Lima E, Menke A, Hanemaaijer R, Keijer J, Salic K, Kleemann R, Morrison MC. Butyrate Protects against Diet-Induced NASH and Liver Fibrosis and Suppresses Specific Non-Canonical TGF-β Signaling Pathways in Human Hepatic Stellate Cells. Biomedicines 2021; 9:biomedicines9121954. [PMID: 34944770 PMCID: PMC8698820 DOI: 10.3390/biomedicines9121954] [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: 12/02/2021] [Revised: 12/16/2021] [Accepted: 12/17/2021] [Indexed: 12/18/2022] Open
Abstract
In obesity-associated non-alcoholic steatohepatitis (NASH), persistent hepatocellular damage and inflammation are key drivers of fibrosis, which is the main determinant of NASH-associated mortality. The short-chain fatty acid butyrate can exert metabolic improvements and anti-inflammatory activities in NASH. However, its effects on NASH-associated liver fibrosis remain unclear. Putative antifibrotic effects of butyrate were studied in Ldlr-/-.Leiden mice fed an obesogenic diet (HFD) containing 2.5% (w/w) butyrate for 38 weeks and compared with a HFD-control group. Antifibrotic mechanisms of butyrate were further investigated in TGF-β-stimulated primary human hepatic stellate cells (HSC). HFD-fed mice developed obesity, insulin resistance, increased plasma leptin levels, adipose tissue inflammation, gut permeability, dysbiosis, and NASH-associated fibrosis. Butyrate corrected hyperinsulinemia, lowered plasma leptin levels, and attenuated adipose tissue inflammation, without affecting gut permeability or microbiota composition. Butyrate lowered plasma ALT and CK-18M30 levels and attenuated hepatic steatosis and inflammation. Butyrate inhibited fibrosis development as demonstrated by decreased hepatic collagen content and Sirius-red-positive area. In TGF-β-stimulated HSC, butyrate dose-dependently reduced collagen deposition and decreased procollagen1α1 and PAI1 protein expression. Transcriptomic analysis and subsequent pathway and upstream regulator analysis revealed deactivation of specific non-canonical TGF-β signaling pathways Rho-like GTPases and PI3K/AKT and other important pro-fibrotic regulators (e.g., YAP/TAZ, MYC) by butyrate, providing a potential rationale for its antifibrotic effects. In conclusion, butyrate protects against obesity development, insulin resistance-associated NASH, and liver fibrosis. These antifibrotic effects are at least partly attributable to a direct effect of butyrate on collagen production in hepatic stellate cells, involving inhibition of non-canonical TGF-β signaling pathways.
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Affiliation(s)
- Eveline Gart
- Department of Metabolic Health Research, The Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands; (W.v.D.); (K.T.); (A.M.); (R.H.); (K.S.); (R.K.); (M.C.M.)
- Human and Animal Physiology, Wageningen University, 6708 WD Wageningen, The Netherlands;
- Correspondence:
| | - Wim van Duyvenvoorde
- Department of Metabolic Health Research, The Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands; (W.v.D.); (K.T.); (A.M.); (R.H.); (K.S.); (R.K.); (M.C.M.)
| | - Karin Toet
- Department of Metabolic Health Research, The Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands; (W.v.D.); (K.T.); (A.M.); (R.H.); (K.S.); (R.K.); (M.C.M.)
| | - Martien P. M. Caspers
- Department of Microbiology and Systems Biology, TNO, 3704 HE Zeist, The Netherlands; (M.P.M.C.); (L.V.); (E.S.L.)
| | - Lars Verschuren
- Department of Microbiology and Systems Biology, TNO, 3704 HE Zeist, The Netherlands; (M.P.M.C.); (L.V.); (E.S.L.)
| | - Mette Juul Nielsen
- Nordic Bioscience, Biomarkers and Research, 2730 Herlev, Denmark; (M.J.N.); (D.J.L.)
| | - Diana Julie Leeming
- Nordic Bioscience, Biomarkers and Research, 2730 Herlev, Denmark; (M.J.N.); (D.J.L.)
| | - Everton Souto Lima
- Department of Microbiology and Systems Biology, TNO, 3704 HE Zeist, The Netherlands; (M.P.M.C.); (L.V.); (E.S.L.)
| | - Aswin Menke
- Department of Metabolic Health Research, The Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands; (W.v.D.); (K.T.); (A.M.); (R.H.); (K.S.); (R.K.); (M.C.M.)
| | - Roeland Hanemaaijer
- Department of Metabolic Health Research, The Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands; (W.v.D.); (K.T.); (A.M.); (R.H.); (K.S.); (R.K.); (M.C.M.)
| | - Jaap Keijer
- Human and Animal Physiology, Wageningen University, 6708 WD Wageningen, The Netherlands;
| | - Kanita Salic
- Department of Metabolic Health Research, The Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands; (W.v.D.); (K.T.); (A.M.); (R.H.); (K.S.); (R.K.); (M.C.M.)
| | - Robert Kleemann
- Department of Metabolic Health Research, The Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands; (W.v.D.); (K.T.); (A.M.); (R.H.); (K.S.); (R.K.); (M.C.M.)
| | - Martine C. Morrison
- Department of Metabolic Health Research, The Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands; (W.v.D.); (K.T.); (A.M.); (R.H.); (K.S.); (R.K.); (M.C.M.)
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Fan X, Yin X, Zhao Q, Yang Y. Hsa_circRNA_0045861 promotes renal injury in ureteropelvic junction obstruction via the microRNA-181d-5p/sirtuin 1 signaling axis. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1571. [PMID: 34790777 PMCID: PMC8576705 DOI: 10.21037/atm-21-5060] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 10/16/2021] [Indexed: 12/16/2022]
Abstract
Background Ureteropelvic junction obstruction (UPJO) is one of the most common causes of hydronephrosis in children. This study explored the effects and the regulatory mechanisms of the circular RNA (circRNA) hsa_circRNA_0045861 (circRNA_0045861) in UPJO. Methods RNA sequencing was used to identify the differentially expressed circRNAs in UPJO. The effects of circRNA_0045861 on renal cell apoptosis was investigated by flow cytometry and Western blot analysis. Furthermore, we used bioinformatics methods to predict the possible target genes of circRNA_0045861. Fluorescence in-situ hybridization and dual-luciferase reporter assays were performed to validate the target genes of circRNA_0045861. Finally, we evaluated the effects of circRNA_0045861 target gene miR-181d-5p on UPJO-induced renal fibrosis in vivo. Results RNA sequencing identified 63 upregulated and 64 downregulated circRNAs in UPJO patients. The expression of circRNA_0045861 was significantly elevated in kidney damage both in vivo and in vitro. Silencing circ_0045861 inhibited transforming growth factor (TGF)-β1-induced apoptosis in vitro in human kidney 2 (HK-2) cells. Furthermore, circ_0045861 was shown to directly interact with the microRNA miR-181d-5p and regulate the expression of sirtuin 1 (SIRT1), thereby promoting the progression of apoptosis and renal injury. In addition, overexpression of miR-181d-5p inhibited cell apoptosis and renal fibrosis in a mouse model through downregulating the SIRT1/p53 pathway. Conclusions Circ_0045861 may be a novel candidate circRNA in the pathogenesis of UPJO by acting as a pro-apoptotic factor via the miR-181d-5p/SIRT1 axis.
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Affiliation(s)
- Xu Fan
- Department of Pediatric Urology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xiaoming Yin
- Department of Pediatric Urology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Qi Zhao
- Department of Pediatric Urology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yi Yang
- Department of Pediatric Urology, Shengjing Hospital of China Medical University, Shenyang, China
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