1
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Youssef KK, Nieto MA. Epithelial-mesenchymal transition in tissue repair and degeneration. Nat Rev Mol Cell Biol 2024; 25:720-739. [PMID: 38684869 DOI: 10.1038/s41580-024-00733-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/26/2024] [Indexed: 05/02/2024]
Abstract
Epithelial-mesenchymal transitions (EMTs) are the epitome of cell plasticity in embryonic development and cancer; during EMT, epithelial cells undergo dramatic phenotypic changes and become able to migrate to form different tissues or give rise to metastases, respectively. The importance of EMTs in other contexts, such as tissue repair and fibrosis in the adult, has become increasingly recognized and studied. In this Review, we discuss the function of EMT in the adult after tissue damage and compare features of embryonic and adult EMT. Whereas sustained EMT leads to adult tissue degeneration, fibrosis and organ failure, its transient activation, which confers phenotypic and functional plasticity on somatic cells, promotes tissue repair after damage. Understanding the mechanisms and temporal regulation of different EMTs provides insight into how some tissues heal and has the potential to open new therapeutic avenues to promote repair or regeneration of tissue damage that is currently irreversible. We also discuss therapeutic strategies that modulate EMT that hold clinical promise in ameliorating fibrosis, and how precise EMT activation could be harnessed to enhance tissue repair.
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Affiliation(s)
| | - M Angela Nieto
- Instituto de Neurociencias (CSIC-UMH), Sant Joan d'Alacant, Spain.
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.
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2
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Wu D, Wu J, Liu H, Shi S, Wang L, Huang Y, Yu X, Lei Z, Ouyang T, Shen J, Wu G, Wang S. A biomimetic renal fibrosis progression model on-chip evaluates anti-fibrotic effects longitudinally in a dynamic fibrogenic niche. LAB ON A CHIP 2023; 23:4708-4725. [PMID: 37840380 DOI: 10.1039/d3lc00393k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/17/2023]
Abstract
Although renal fibrosis can advance chronic kidney disease and progressively lead to end-stage renal failure, no effective anti-fibrotic drugs have been clinically approved. To aid drug development, we developed a biomimetic renal fibrosis progression model on-chip to evaluate anti-fibrotic effects of natural killer cell-derived extracellular vesicles and pirfenidone (PFD) across different fibrotic stages. First, the dynamic interplay between fibroblasts and kidney-derived extracellular matrix (ECM) resembling the fibrogenic niche on-chip demonstrated that myofibroblasts induced by stiff ECM in 3 days were reversed to fibroblasts by switching to soft ECM, which was within 2, but not 7 days. Second, PFD significantly down-regulated the expression of α-SMA in NRK-49F in medium ECM, as opposed to stiff ECM. Third, a study in rats showed that early administration of PFD significantly inhibited renal fibrosis in terms of the expression levels of α-SMA and YAP. Taken together, both on-chip and animal models indicate the importance of early anti-fibrotic intervention for checking the progression of renal fibrosis. Therefore, this renal fibrosis progression on-chip with a feature of recapitulating dynamic biochemical and biophysical cues can be readily used to assess anti-fibrotic candidates and to explore the tipping point when the fibrotic fate can be rescued for better medical intervention.
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Affiliation(s)
- Di Wu
- Institute for Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, 310029, China
- Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China
- Tianfu Jincheng Laboratory, City of Future Medicine, Chengdu, 641400, China
| | - Jianguo Wu
- Institute for Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, 310029, China
| | - Hui Liu
- Institute for Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, 310029, China
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610065, China
- Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, 610065, China
| | - Shengyu Shi
- Institute for Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, 310029, China
| | - Liangwen Wang
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yixiao Huang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610065, China
- Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, 610065, China
| | - Xiaorui Yu
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610065, China
- Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, 610065, China
| | - Zhuoyue Lei
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610065, China
- Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, 610065, China
| | - Tanliang Ouyang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610065, China
- Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, 610065, China
| | - Jia Shen
- Kidney Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310029, China
| | - Guohua Wu
- Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610065, China
- Tianfu Jincheng Laboratory, City of Future Medicine, Chengdu, 641400, China
| | - Shuqi Wang
- Institute for Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, 310029, China
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610065, China
- Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, 610065, China
- Tianfu Jincheng Laboratory, City of Future Medicine, Chengdu, 641400, China
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3
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Guo L, Zhang Y, Lu J, Li X, Zhang C, Song W, Dong Y, Zhou X, Li R. Nicotine promotes renal interstitial fibrosis via upregulation of XIAP in an alpha7-nAChR-dependent manner. Mol Cell Endocrinol 2023; 576:111989. [PMID: 37451424 DOI: 10.1016/j.mce.2023.111989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/26/2023] [Accepted: 06/12/2023] [Indexed: 07/18/2023]
Abstract
Renal fibrosis, characterized by excessive accumulation of the extracellular matrix in the renal tubulointerstitium, can lead to chronic kidney disease (CKD), resulting in a heavy burden on families and society. Clinical studies have shown that smoking is closely associated with CKD deterioration in patients with diabetes, hypertension, polycystic kidney disease, and kidney transplantation. However, the mechanism of action of nicotine in renal fibrosis pathogenesis remains largely unknown. X-linked inhibitor of apoptosis (XIAP), a member of the inhibitor of apoptosis protein (IAP) family, is involved in apoptosis, necroptosis, autophagy, and immune response. Here, the upregulated expression of XIAP and α7 nicotine acetylcholine receptor (α7-nAChR) was determined in the kidneys of the CKD smoking group in human and animal studies. A significant positive correlation between XIAP and cotinine was observed. In addition, the nuclear translocation and transcriptional activity of SP1 were promoted when nicotine bound to α7-nAChR, resulting in XIAP overexpression and renal interstitial fibrosis progression. This phenotype can be reversed by the nicotine receptor subtype α7-nAChR antagonists methyllycaconitine. Our results revealed the complex underlying mechanism of nicotine in promoting renal fibrosis by altering SP1 nucleocytoplasmic translocation and regulating XIAP expression. These results provide novel insights into the pathogenesis and treatment of CKD.
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Affiliation(s)
- Lili Guo
- Shanxi Provincial Key Laboratory of Kidney Disease, Shanxi Provincial People's Hospital, Taiyuan, China; Department of Nephrology, Shanxi Provincial People's Hospital, Taiyuan, China.
| | - Yue Zhang
- The Fifth Clinical Medical College of Shanxi Medical University, Fifth Hospital of Shanxi Medical University, Taiyuan, China
| | - Jian Lu
- Shanxi Provincial Key Laboratory of Kidney Disease, Shanxi Provincial People's Hospital, Taiyuan, China; Department of Nephrology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Xiaoyang Li
- Shanxi Provincial Key Laboratory of Kidney Disease, Shanxi Provincial People's Hospital, Taiyuan, China
| | - Chao Zhang
- The Fifth Clinical Medical College of Shanxi Medical University, Fifth Hospital of Shanxi Medical University, Taiyuan, China
| | - Wenzhu Song
- School of Public Health, Shanxi Medical University, Taiyuan, China
| | - Yafang Dong
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, China
| | - Xiangyang Zhou
- Preclinical-medicine of Shanxi Medical University, Taiyuan, China
| | - Rongshan Li
- Shanxi Provincial Key Laboratory of Kidney Disease, Shanxi Provincial People's Hospital, Taiyuan, China; Department of Nephrology, Shanxi Provincial People's Hospital, Taiyuan, China.
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4
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Haerinck J, Goossens S, Berx G. The epithelial-mesenchymal plasticity landscape: principles of design and mechanisms of regulation. Nat Rev Genet 2023; 24:590-609. [PMID: 37169858 DOI: 10.1038/s41576-023-00601-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/30/2023] [Indexed: 05/13/2023]
Abstract
Epithelial-mesenchymal plasticity (EMP) enables cells to interconvert between several states across the epithelial-mesenchymal landscape, thereby acquiring hybrid epithelial/mesenchymal phenotypic features. This plasticity is crucial for embryonic development and wound healing, but also underlies the acquisition of several malignant traits during cancer progression. Recent research using systems biology and single-cell profiling methods has provided novel insights into the main forces that shape EMP, which include the microenvironment, lineage specification and cell identity, and the genome. Additionally, key roles have emerged for hysteresis (cell memory) and cellular noise, which can drive stochastic transitions between cell states. Here, we review these forces and the distinct but interwoven layers of regulatory control that stabilize EMP states or facilitate epithelial-mesenchymal transitions (EMTs) and discuss the therapeutic potential of manipulating the EMP landscape.
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Affiliation(s)
- Jef Haerinck
- Molecular and Cellular Oncology Laboratory, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Steven Goossens
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
- Unit for Translational Research in Oncology, Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | - Geert Berx
- Molecular and Cellular Oncology Laboratory, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
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5
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Gluba-Sagr A, Franczyk B, Rysz-Górzyńska M, Ławiński J, Rysz J. The Role of miRNA in Renal Fibrosis Leading to Chronic Kidney Disease. Biomedicines 2023; 11:2358. [PMID: 37760798 PMCID: PMC10525803 DOI: 10.3390/biomedicines11092358] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 08/14/2023] [Accepted: 08/19/2023] [Indexed: 09/29/2023] Open
Abstract
Chronic kidney disease (CKD) is an important health concern that is expected to be the fifth most widespread cause of death worldwide by 2040. The presence of chronic inflammation, oxidative stress, ischemia, etc., stimulates the development and progression of CKD. Tubulointerstitial fibrosis is a common pathomechanism of renal dysfunction, irrespective of the primary origin of renal injury. With time, fibrosis leads to end-stage renal disease (ESRD). Many studies have demonstrated that microRNAs (miRNAs, miRs) are involved in the onset and development of fibrosis and CKD. miRNAs are vital regulators of some pathophysiological processes; therefore, their utility as therapeutic agents in various diseases has been suggested. Several miRNAs were demonstrated to participate in the development and progression of kidney disease. Since renal fibrosis is an important problem in chronic kidney disease, many scientists have focused on the determination of miRNAs associated with kidney fibrosis. In this review, we present the role of several miRNAs in renal fibrosis and the potential pathways involved. However, as well as those mentioned above, other miRs have also been suggested to play a role in this process in CKD. The reports concerning the impact of some miRNAs on fibrosis are conflicting, probably because the expression and regulation of miRNAs occur in a tissue- and even cell-dependent manner. Moreover, different assessment modes and populations have been used. There is a need for large studies and clinical trials to confirm the role of miRs in a clinical setting. miRNAs have great potential; thus, their analysis may improve diagnostic and therapeutic strategies.
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Affiliation(s)
- Anna Gluba-Sagr
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, 90-549 Lodz, Poland
| | - Beata Franczyk
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, 90-549 Lodz, Poland
| | - Magdalena Rysz-Górzyńska
- Department of Ophthalmology and Visual Rehabilitation, Medical University of Lodz, 90-549 Lodz, Poland
| | - Janusz Ławiński
- Department of Urology, Institute of Medical Sciences, College of Medical Sciences, University of Rzeszow, 35-055 Rzeszow, Poland
| | - Jacek Rysz
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, 90-549 Lodz, Poland
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6
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Huang R, Fu P, Ma L. Kidney fibrosis: from mechanisms to therapeutic medicines. Signal Transduct Target Ther 2023; 8:129. [PMID: 36932062 PMCID: PMC10023808 DOI: 10.1038/s41392-023-01379-7] [Citation(s) in RCA: 182] [Impact Index Per Article: 91.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 02/12/2023] [Accepted: 02/20/2023] [Indexed: 03/19/2023] Open
Abstract
Chronic kidney disease (CKD) is estimated to affect 10-14% of global population. Kidney fibrosis, characterized by excessive extracellular matrix deposition leading to scarring, is a hallmark manifestation in different progressive CKD; However, at present no antifibrotic therapies against CKD exist. Kidney fibrosis is identified by tubule atrophy, interstitial chronic inflammation and fibrogenesis, glomerulosclerosis, and vascular rarefaction. Fibrotic niche, where organ fibrosis initiates, is a complex interplay between injured parenchyma (like tubular cells) and multiple non-parenchymal cell lineages (immune and mesenchymal cells) located spatially within scarring areas. Although the mechanisms of kidney fibrosis are complicated due to the kinds of cells involved, with the help of single-cell technology, many key questions have been explored, such as what kind of renal tubules are profibrotic, where myofibroblasts originate, which immune cells are involved, and how cells communicate with each other. In addition, genetics and epigenetics are deeper mechanisms that regulate kidney fibrosis. And the reversible nature of epigenetic changes including DNA methylation, RNA interference, and chromatin remodeling, gives an opportunity to stop or reverse kidney fibrosis by therapeutic strategies. More marketed (e.g., RAS blockage, SGLT2 inhibitors) have been developed to delay CKD progression in recent years. Furthermore, a better understanding of renal fibrosis is also favored to discover biomarkers of fibrotic injury. In the review, we update recent advances in the mechanism of renal fibrosis and summarize novel biomarkers and antifibrotic treatment for CKD.
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Affiliation(s)
- Rongshuang Huang
- Kidney Research Institute, Division of Nephrology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Ping Fu
- Kidney Research Institute, Division of Nephrology, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Liang Ma
- Kidney Research Institute, Division of Nephrology, West China Hospital, Sichuan University, Chengdu, 610041, China.
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7
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Sundararajan V, Burk UC, Bajdak-Rusinek K. Revisiting the miR-200 Family: A Clan of Five Siblings with Essential Roles in Development and Disease. Biomolecules 2022; 12:biom12060781. [PMID: 35740906 PMCID: PMC9221129 DOI: 10.3390/biom12060781] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/29/2022] [Accepted: 06/01/2022] [Indexed: 12/07/2022] Open
Abstract
Over two decades of studies on small noncoding RNA molecules illustrate the significance of microRNAs (miRNAs/miRs) in controlling multiple physiological and pathological functions through post-transcriptional and spatiotemporal gene expression. Among the plethora of miRs that are essential during animal embryonic development, in this review, we elaborate the indispensable role of the miR-200 family (comprising miR-200a, -200b, 200c, -141, and -429) in governing the cellular functions associated with epithelial homeostasis, such as epithelial differentiation and neurogenesis. Additionally, in pathological contexts, miR-200 family members are primarily involved in tumor-suppressive roles, including the reversal of the cancer-associated epithelial–mesenchymal transition dedifferentiation process, and are dysregulated during organ fibrosis. Moreover, recent eminent studies have elucidated the crucial roles of miR-200s in the pathophysiology of multiple neurodegenerative diseases and tissue fibrosis. Lastly, we summarize the key studies that have recognized the potential use of miR-200 members as biomarkers for the diagnosis and prognosis of cancers, elaborating the application of these small biomolecules in aiding early cancer detection and intervention.
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Affiliation(s)
- Vignesh Sundararajan
- Cancer Science Institute of Singapore, National University of Singapore, Center for Translational Medicine, Singapore 117599, Singapore;
| | - Ulrike C. Burk
- Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany;
| | - Karolina Bajdak-Rusinek
- Department of Medical Genetics, Faculty of Medical Sciences, Medical University of Silesia, 40-752 Katowice, Poland
- Correspondence: ; Tel.: +48-32-208-8382
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8
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Liu G, Liu X, Yang Y. Comparative transcriptome analysis of miRNA in hydronephrosis male children caused by ureteropelvic junction obstruction with or without renal functional injury. PeerJ 2022; 10:e12962. [PMID: 35237468 PMCID: PMC8884061 DOI: 10.7717/peerj.12962] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 01/27/2022] [Indexed: 01/11/2023] Open
Abstract
MicroRNAs (miRNAs or miRs) are non-coding RNAs that contribute to pathological processes of various kidney diseases. Renal function injury represents a final common outcome of congenital obstructive nephropathy and has attracted a great deal of attention. However the molecular mechanisms are still not fully established. In this study, we compared transcriptome sequencing data of miRNAs of renal tissues from congenital hydronephrosis children with or without renal functional injury, in order to better understand whether microRNAs could play important roles in renal functional injury after ureteropelvic junction obstruction. A total of 22 microRNAs with significant changes in their expression were identified. Five microRNAs were up-regulated and 17 microRNAs were down-regulated in the renal tissues of the hydronephrosis patients with renal function injury compared with those without renal function injury. MicroRNA target genes were predicted by three major online miRNA target prediction algorithms, and all these mRNAs were used to perform the gene ontology analysis and Kyoto Encyclopedia of Gene and Genomes pathway analysis. Then, twelve candidate human and rat homologous miRNAs were selected for validation using RT-qPCR in vitro and in vivo; only miR-187-3p had a trend identical to that detected by the sequencing results among the human tissues, in vivo and in vitro experimental models. In addition, we found that the change of miR-187-3p in vivo was consistent with results in vitro models and showed a decrease trend in time dependence. These results provided a detailed catalog of candidate miRNAs to investigate their regulatory role in renal injury of congenital hydronephrosis, indicating that they may serve as candidate biomarkers or therapeutic targets in the future.
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Affiliation(s)
- Ge Liu
- Urology Division, Pediatric Surgery Department, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China
| | - Xin Liu
- Urology Division, Pediatric Surgery Department, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China
| | - Yi Yang
- Urology Division, Pediatric Surgery Department, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China
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9
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Prado LG, Barbosa AS. Understanding the Renal Fibrotic Process in Leptospirosis. Int J Mol Sci 2021; 22:ijms221910779. [PMID: 34639117 PMCID: PMC8509513 DOI: 10.3390/ijms221910779] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/29/2021] [Accepted: 10/02/2021] [Indexed: 12/12/2022] Open
Abstract
Leptospirosis is a neglected infectious disease caused by pathogenic species of the genus Leptospira. The acute disease is well-described, and, although it resembles other tropical diseases, it can be diagnosed through the use of serological and molecular methods. While the chronic renal disease, carrier state, and kidney fibrosis due to Leptospira infection in humans have been the subject of discussion by researchers, the mechanisms involved in these processes are still overlooked, and relatively little is known about the establishment and maintenance of the chronic status underlying this infectious disease. In this review, we highlight recent findings regarding the cellular communication pathways involved in the renal fibrotic process, as well as the relationship between renal fibrosis due to leptospirosis and CKD/CKDu.
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Affiliation(s)
- Luan Gavião Prado
- Laboratório de Bacteriologia, Instituto Butantan, Avenida Vital Brasil, 1500, São Paulo 05503-900, Brazil;
- Departamento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Avenida Lineu Prestes 1374, São Paulo 05508-000, Brazil
| | - Angela Silva Barbosa
- Laboratório de Bacteriologia, Instituto Butantan, Avenida Vital Brasil, 1500, São Paulo 05503-900, Brazil;
- Correspondence:
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10
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Li H, Chou P, Du F, Sun L, Liu J, Wang W. RETRACTED: Depleting microRNA-183-3p improves renal tubulointerstitial fibrosis after acute kidney injury via SIRT1/PUMA/FOXO3a deacetylation. Life Sci 2021; 269:119017. [PMID: 33450262 DOI: 10.1016/j.lfs.2021.119017] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 12/31/2020] [Accepted: 01/04/2021] [Indexed: 11/28/2022]
Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. Concern was raised about the reliability of the Western blot results in Figs. 2E, and 3C, which appear to have the same eyebrow shaped phenotype as many other publications tabulated here (https://docs.google.com/spreadsheets/d/149EjFXVxpwkBXYJOnOHb6RhAqT4a2llhj9LM60MBffM/edit#gid=0). The journal requested the corresponding author comment on these concerns and provide the raw data. However the authors were not able to satisfactorily fulfil this request and therefore the Editor-in-Chief decided to retract the article.
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Affiliation(s)
- Hunian Li
- Emergency and Critical Care Center, Renmin Hospital, Hubei University of Medicine, Shiyan 442000, Hubei, China
| | - Ping Chou
- Department of Nephrology, Renmin Hospital, Hubei University of Medicine, Shiyan 442000, Hubei, China
| | - Fang Du
- Emergency and Critical Care Center, Renmin Hospital, Hubei University of Medicine, Shiyan 442000, Hubei, China
| | - Liang Sun
- Emergency and Critical Care Center, Renmin Hospital, Hubei University of Medicine, Shiyan 442000, Hubei, China
| | - Jie Liu
- Emergency and Critical Care Center, Renmin Hospital, Hubei University of Medicine, Shiyan 442000, Hubei, China.
| | - Wei Wang
- Department of Nephrology, Renmin Hospital, Hubei University of Medicine, Shiyan 442000, Hubei, China.
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11
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Bai L, Lin Y, Xie J, Zhang Y, Wang H, Zheng D. MiR-27b-3p inhibits the progression of renal fibrosis via suppressing STAT1. Hum Cell 2021; 34:383-393. [PMID: 33454903 PMCID: PMC7900087 DOI: 10.1007/s13577-020-00474-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 12/14/2020] [Indexed: 01/02/2023]
Abstract
Renal fibrosis is a pathologic change in chronic kidney disease (CKD). MicroRNAs (miRNAs) have been shown to play an important role in the development of renal fibrosis. However, the biological role of miR-27b-3p in renal fibrosis remains unclear. Thus, this study aimed to investigate the role of miR-27b-3p in the progression of renal fibrosis. In this study, HK-2 cells were stimulated with transforming growth factor (TGF)-β1 for mimicking fibrosis progression in vitro. The unilateral ureteric obstruction (UUO)-induced mice renal fibrosis in vivo was established as well. The results indicated that the overexpression of miR-27b-3p significantly inhibited epithelial-to-mesenchymal transition (EMT) in TGF-β1-stimulated HK-2 cells, as shown by the decreased expressions of α-SMA, collagen III, Fibronectin and Vimentin. In addition, overexpression of miR-27b-3p markedly decreased TGF-β1-induced apoptosis in HK-2 cells, as evidenced by the decreased levels of Fas, active caspase 8 and active caspase 3. Meanwhile, dual-luciferase assay showed that miR-27b-3p downregulated signal transducers and activators of transcription 1 (STAT1) expression through direct binding with the 3′-UTR of STAT1. Furthermore, overexpression of miR-27b-3p attenuated UUO-induced renal fibrosis via downregulation of STAT1, α-SMA and collagen III. In conclusion, miR-27b-3p overexpression could alleviate renal fibrosis via suppressing STAT1 in vivo and in vitro. Therefore, miR-27b-3p might be a promising therapeutic target for the treatment of renal fibrosis.
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Affiliation(s)
- Lin Bai
- Department of Nephrology, Affiliated Huai'an Hospital of Xuzhou Medical University, 62# Huaihai South Road, Huai'an, 223001, Jiangsu, People's Republic of China
| | - Yongtao Lin
- Department of Nephrology, Affiliated Huai'an Hospital of Xuzhou Medical University, 62# Huaihai South Road, Huai'an, 223001, Jiangsu, People's Republic of China
| | - Juan Xie
- Department of Nephrology, Affiliated Huai'an Hospital of Xuzhou Medical University, 62# Huaihai South Road, Huai'an, 223001, Jiangsu, People's Republic of China
| | - Yiyuan Zhang
- Xuzhou Medical University, Xuzhou, 221004, Jiangsu, People's Republic of China
| | - Hongwu Wang
- Department of Nephrology, Affiliated Huai'an Hospital of Xuzhou Medical University, 62# Huaihai South Road, Huai'an, 223001, Jiangsu, People's Republic of China.
| | - Donghui Zheng
- Department of Nephrology, Affiliated Huai'an Hospital of Xuzhou Medical University, 62# Huaihai South Road, Huai'an, 223001, Jiangsu, People's Republic of China.
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12
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Sakuma H, Hagiwara S, Kantharidis P, Gohda T, Suzuki Y. Potential Targeting of Renal Fibrosis in Diabetic Kidney Disease Using MicroRNAs. Front Pharmacol 2020; 11:587689. [PMID: 33364960 PMCID: PMC7751689 DOI: 10.3389/fphar.2020.587689] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023] Open
Abstract
Diabetic kidney disease (DKD) is a major health problem and one of the leading causes of end-stage renal disease worldwide. Despite recent advances, there exists an urgent need for the development of new treatments for DKD. DKD is characterized by the excessive synthesis and deposition of extracellular matrix proteins in glomeruli and the tubulointerstitium, ultimately leading to glomerulosclerosis as well as interstitial fibrosis. Renal fibrosis is the final common pathway at the histological level leading to an end-stage renal failure. In fact, activation of the nuclear factor erythroid 2-related factor 2 pathway by bardoxolone methyl and inhibition of transforming growth factor beta signaling by pirfenidone have been assumed to be effective therapeutic targets for DKD, and various basic and clinical studies are currently ongoing. MicroRNAs (miRNAs) are endogenously produced small RNA molecules of 18–22 nucleotides in length, which act as posttranscriptional repressors of gene expression. Studies have demonstrated that several miRNAs contribute to renal fibrosis. In this review, we outline the potential of using miRNAs as an antifibrosis treatment strategy and discuss their clinical application in DKD.
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Affiliation(s)
- Hiroko Sakuma
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Shinji Hagiwara
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan.,Department of Kidney and Hypertension, Juntendo Tokyo Koto Geriatric Medical Center, Tokyo, Japan
| | | | - Tomohito Gohda
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Yusuke Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
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13
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Yarahmadi A, Shahrokhi SZ, Mostafavi-Pour Z, Azarpira N. MicroRNAs in diabetic nephropathy: From molecular mechanisms to new therapeutic targets of treatment. Biochem Pharmacol 2020; 189:114301. [PMID: 33203517 DOI: 10.1016/j.bcp.2020.114301] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 10/20/2020] [Accepted: 10/21/2020] [Indexed: 12/16/2022]
Abstract
Despite considerable investigation in diabetic nephropathy (DN) pathogenesis and possible treatments, current therapies still do not provide competent prevention from disease progression to end-stage renal disease (ESRD) in most patients. Therefore, investigating exact molecular mechanisms and important mediators underlying DN may help design better therapeutic approaches for proper treatment. MicroRNAs (MiRNAs) are a class of small non-coding RNAs that play a crucial role in post-transcriptional regulation of many gene expression within the cells and present an excellent opportunity for new therapeutic approaches because their profile is often changed during many diseases, including DN. This review discusses the most important signaling pathways involved in DN and changes in miRNAs profile in each signaling pathway. We also suggest possible approaches for miRNA derived interventions for designing better treatment of DN.
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Affiliation(s)
- Amir Yarahmadi
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyedeh Zahra Shahrokhi
- Department of Laboratory Medicine, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zohreh Mostafavi-Pour
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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14
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Hamada-Tsutsumi S, Onishi M, Matsuura K, Isogawa M, Kawashima K, Sato Y, Tanaka Y. Inhibitory Effect of a Human MicroRNA, miR-6133-5p, on the Fibrotic Activity of Hepatic Stellate Cells in Culture. Int J Mol Sci 2020; 21:ijms21197251. [PMID: 33019495 PMCID: PMC7583928 DOI: 10.3390/ijms21197251] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 09/25/2020] [Accepted: 09/28/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND We recently identified 39 human microRNAs, which effectively suppress hepatitis B virus (HBV) replication in hepatocytes. Chronic HBV infection often results in active, hepatitis-related liver fibrosis; hence, we assessed whether any of these microRNAs have anti-fibrotic potential and predicted that miR-6133-5p may target several fibrosis-related genes. METHODS The hepatic stellate cell line LX-2 was transfected with an miR-6133-5p mimic and subsequently treated with Transforming growth factor (TGF)-β. The mRNA and protein products of the COL1A1 gene, encoding collagen, and the ACTA2 gene, an activation marker of hepatic stellate cells, were quantified. RESULTS The expression of COL1A1 and ACTA2 was markedly reduced in LX-2 cells treated with miR-6133-5p. Interestingly, phosphorylation of c-Jun N-terminal kinase (JNK) was also significantly decreased by miR-6133-5p treatment. The expression of several predicted target genes of miR-6133-5p, including TGFBR2 (which encodes Transforming Growth Factor Beta Receptor 2) and FGFR1 (which encodes Fibroblast Growth Factor Receptor 1), was also reduced in miR-6133-5p-treated cells. The knockdown of TGFBR2 by the corresponding small interfering RNA greatly suppressed the expression of COL1A1 and ACTA2. Treatment with the JNK inhibitor, SP600125, also suppressed COL1A1 and ACTA2 expression, indicating that TGFBR2 and JNK mediate the anti-fibrotic effect of miR-6133-5p. The downregulation of FGFR1 may result in a decrease of phosphorylated Akt, ERK (extracellular signal-regulated kinase), and JNK. CONCLUSION miR-6133-5p has a strong anti-fibrotic effect, mediated by inactivation of TGFBR2, Akt, and JNK.
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MESH Headings
- Actins/genetics
- Actins/metabolism
- Anthracenes/pharmacology
- Cell Differentiation/drug effects
- Cell Line, Transformed
- Cell Proliferation/drug effects
- Collagen Type I/genetics
- Collagen Type I/metabolism
- Collagen Type I, alpha 1 Chain
- Fibroblasts/drug effects
- Fibroblasts/metabolism
- Fibroblasts/pathology
- Gene Expression Regulation
- Hepatic Stellate Cells/cytology
- Hepatic Stellate Cells/drug effects
- Hepatic Stellate Cells/metabolism
- Humans
- MAP Kinase Kinase 4/antagonists & inhibitors
- MAP Kinase Kinase 4/genetics
- MAP Kinase Kinase 4/metabolism
- MicroRNAs/agonists
- MicroRNAs/antagonists & inhibitors
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Mitogen-Activated Protein Kinase 1/genetics
- Mitogen-Activated Protein Kinase 1/metabolism
- Mitogen-Activated Protein Kinase 3/genetics
- Mitogen-Activated Protein Kinase 3/metabolism
- Oligoribonucleotides/genetics
- Oligoribonucleotides/metabolism
- Protein Kinase Inhibitors/pharmacology
- Proto-Oncogene Proteins c-akt/antagonists & inhibitors
- Proto-Oncogene Proteins c-akt/genetics
- Proto-Oncogene Proteins c-akt/metabolism
- RNA, Small Interfering/genetics
- RNA, Small Interfering/metabolism
- Receptor, Fibroblast Growth Factor, Type 1/genetics
- Receptor, Fibroblast Growth Factor, Type 1/metabolism
- Receptor, Transforming Growth Factor-beta Type II/antagonists & inhibitors
- Receptor, Transforming Growth Factor-beta Type II/genetics
- Receptor, Transforming Growth Factor-beta Type II/metabolism
- Signal Transduction
- Transforming Growth Factor beta/pharmacology
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Affiliation(s)
- Susumu Hamada-Tsutsumi
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan; (S.H.-T.); (M.O.); (M.I.); (K.K.)
| | - Masaya Onishi
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan; (S.H.-T.); (M.O.); (M.I.); (K.K.)
| | - Kentaro Matsuura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan;
| | - Masanori Isogawa
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan; (S.H.-T.); (M.O.); (M.I.); (K.K.)
| | - Keigo Kawashima
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan; (S.H.-T.); (M.O.); (M.I.); (K.K.)
| | - Yusuke Sato
- Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan;
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan; (S.H.-T.); (M.O.); (M.I.); (K.K.)
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
- Correspondence: ; Tel.: +81-96-373-5146
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15
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Peters LJF, Floege J, Biessen EAL, Jankowski J, van der Vorst EPC. MicroRNAs in Chronic Kidney Disease: Four Candidates for Clinical Application. Int J Mol Sci 2020; 21:E6547. [PMID: 32906849 PMCID: PMC7555601 DOI: 10.3390/ijms21186547] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/31/2020] [Accepted: 09/04/2020] [Indexed: 12/13/2022] Open
Abstract
There are still major challenges regarding the early diagnosis and treatment of chronic kidney disease (CKD), which is in part due to the fact that its pathophysiology is very complex and not clarified in detail. The diagnosis of CKD commonly is made after kidney damage has occurred. This highlights the need for better mechanistic insight into CKD as well as improved clinical tools for both diagnosis and treatment. In the last decade, many studies have focused on microRNAs (miRs) as novel diagnostic tools or clinical targets. MiRs are small non-coding RNA molecules that are involved in post-transcriptional gene regulation and many have been studied in CKD. A wide array of pre-clinical and clinical studies have highlighted the potential role for miRs in the pathogenesis of hypertensive nephropathy, diabetic nephropathy, glomerulonephritis, kidney tubulointerstitial fibrosis, and some of the associated cardiovascular complications. In this review, we will provide an overview of the miRs studied in CKD, especially highlighting miR-103a-3p, miR-192-5p, the miR-29 family and miR-21-5p as these have the greatest potential to result in novel therapeutic and diagnostic strategies.
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Affiliation(s)
- Linsey J. F. Peters
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University Hospital, 52074 Aachen, Germany; (L.J.F.P.); (E.A.L.B.); (J.J.)
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, 6229 ER Maastricht, The Netherlands
- Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University Hospital, 52074 Aachen, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, 80336 Munich, Germany
| | - Jürgen Floege
- Division of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, 52074 Aachen, Germany;
| | - Erik A. L. Biessen
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University Hospital, 52074 Aachen, Germany; (L.J.F.P.); (E.A.L.B.); (J.J.)
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, 6229 ER Maastricht, The Netherlands
| | - Joachim Jankowski
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University Hospital, 52074 Aachen, Germany; (L.J.F.P.); (E.A.L.B.); (J.J.)
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, 6229 ER Maastricht, The Netherlands
| | - Emiel P. C. van der Vorst
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University Hospital, 52074 Aachen, Germany; (L.J.F.P.); (E.A.L.B.); (J.J.)
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, 6229 ER Maastricht, The Netherlands
- Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University Hospital, 52074 Aachen, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, 80336 Munich, Germany
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, 80336 Munich, Germany
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16
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Yang J, Antin P, Berx G, Blanpain C, Brabletz T, Bronner M, Campbell K, Cano A, Casanova J, Christofori G, Dedhar S, Derynck R, Ford HL, Fuxe J, García de Herreros A, Goodall GJ, Hadjantonakis AK, Huang RYJ, Kalcheim C, Kalluri R, Kang Y, Khew-Goodall Y, Levine H, Liu J, Longmore GD, Mani SA, Massagué J, Mayor R, McClay D, Mostov KE, Newgreen DF, Nieto MA, Puisieux A, Runyan R, Savagner P, Stanger B, Stemmler MP, Takahashi Y, Takeichi M, Theveneau E, Thiery JP, Thompson EW, Weinberg RA, Williams ED, Xing J, Zhou BP, Sheng G. Guidelines and definitions for research on epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 2020; 21:341-352. [PMID: 32300252 PMCID: PMC7250738 DOI: 10.1038/s41580-020-0237-9] [Citation(s) in RCA: 1222] [Impact Index Per Article: 244.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/11/2020] [Indexed: 02/06/2023]
Abstract
Epithelial–mesenchymal transition (EMT) encompasses dynamic changes in cellular organization from epithelial to mesenchymal phenotypes, which leads to functional changes in cell migration and invasion. EMT occurs in a diverse range of physiological and pathological conditions and is driven by a conserved set of inducing signals, transcriptional regulators and downstream effectors. With over 5,700 publications indexed by Web of Science in 2019 alone, research on EMT is expanding rapidly. This growing interest warrants the need for a consensus among researchers when referring to and undertaking research on EMT. This Consensus Statement, mediated by ‘the EMT International Association’ (TEMTIA), is the outcome of a 2-year-long discussion among EMT researchers and aims to both clarify the nomenclature and provide definitions and guidelines for EMT research in future publications. We trust that these guidelines will help to reduce misunderstanding and misinterpretation of research data generated in various experimental models and to promote cross-disciplinary collaboration to identify and address key open questions in this research field. While recognizing the importance of maintaining diversity in experimental approaches and conceptual frameworks, we emphasize that lasting contributions of EMT research to increasing our understanding of developmental processes and combatting cancer and other diseases depend on the adoption of a unified terminology to describe EMT. In this Consensus Statement, the authors (on behalf of the EMT International Association) propose guidelines to define epithelial–mesenchymal transition, its phenotypic plasticity and the associated multiple intermediate epithelial–mesenchymal cell states. Clarification of nomenclature and definitions will help reduce misinterpretation of research data generated in different experimental model systems and promote cross-disciplinary collaboration.
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Affiliation(s)
- Jing Yang
- Departments of Pharmacology and Pediatrics, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
| | - Parker Antin
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA
| | - Geert Berx
- Molecular and Cellular Oncology Lab, Department of Biomedical Molecular Biology, Ghent University, Cancer Research Institute Ghent (CRIG), VIB Center for Inflammation Research, Ghent, Belgium
| | - Cédric Blanpain
- Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles, Bruxelles, Belgium
| | - Thomas Brabletz
- Department of Experimental Medicine 1, Nikolaus-Fiebiger-Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Marianne Bronner
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Kyra Campbell
- Department of Biomedical Science and Bateson Centre, University of Sheffield, Sheffield, UK
| | - Amparo Cano
- Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), IdiPAZ & Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Jordi Casanova
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology/Institut de Biologia Molecular de Barcelona (IBMB-CSIC), Barcelona, Spain
| | | | - Shoukat Dedhar
- Department of Biochemistry and Molecular Biology, University of British Columbia and British Columbia Cancer Research Centre, Vancouver, BC, Canada
| | - Rik Derynck
- Departments of Cell and Tissue Biology, and Anatomy, University of California at San Francisco, San Francisco, CA, USA
| | - Heide L Ford
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Jonas Fuxe
- Department of Laboratory Medicine (LABMED), Division of Pathology, Karolinska University Hospital and Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
| | - Antonio García de Herreros
- Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM) and Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain
| | - Gregory J Goodall
- Centre for Cancer Biology, An alliance of SA Pathology and University of South Australia, Adelaide, SA, Australia
| | - Anna-Katerina Hadjantonakis
- Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ruby Y J Huang
- School of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chaya Kalcheim
- Department of Medical Neurobiology, Institute for medical Research Israel-Canada and the Safra Center for Neurosciences, Hebrew University of Jerusalem, Hadassah Medical School, Jerusalem, Israel
| | - Raghu Kalluri
- Department of Cancer Biology, Metastasis Research Center, MD Anderson Cancer Center, Houston, TX, USA
| | - Yibin Kang
- Department of Molecular Biology, Princeton University, Princeton, NJ, USA
| | - Yeesim Khew-Goodall
- Centre for Cancer Biology, an Alliance of SA Pathology and the University of South Australia, Adelaide, SA, Australia
| | - Herbert Levine
- Department of Physics, Northeastern University, Boston, MA, USA
| | - Jinsong Liu
- Department of Anatomic Pathology, The Division of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Gregory D Longmore
- Department of Medicine (Oncology) and Department of Cell Biology and Physiology, ICCE Institute, Washington University, St. Louis, MO, USA
| | - Sendurai A Mani
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Joan Massagué
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Roberto Mayor
- Department of Cell and Developmental Biology, University College London, London, UK
| | - David McClay
- Department of Biology, Duke University, Durham, NC, USA
| | - Keith E Mostov
- Departments of Anatomy and Biochemistry/Biophysics, University of California, San Francisco, School of Medicine, San Francisco, CA, USA
| | - Donald F Newgreen
- Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC, Australia
| | - M Angela Nieto
- Instituto de Neurociencias (CSIC-UMH) Avda Ramon y Cajal s/n, Sant Joan d´Alacant, Spain
| | - Alain Puisieux
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Lyon, France.,Institut Curie, PSL Research University, Paris, France
| | - Raymond Runyan
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA
| | - Pierre Savagner
- INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, University Paris-Saclay, Villejuif, France
| | - Ben Stanger
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Marc P Stemmler
- Department of Experimental Medicine 1, Nikolaus-Fiebiger-Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Yoshiko Takahashi
- Department of Zoology, Graduate School of Science, Kyoto University, Kyoto, Japan
| | | | - Eric Theveneau
- Centre de Biologie du Développement (CBD), Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Jean Paul Thiery
- Guangzhou Regenerative Medicine and Health, Guangdong Laboratory, Guangzhou, China
| | - Erik W Thompson
- School of Biomedical Sciences and Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Woolloongabba, QLD, Australia
| | - Robert A Weinberg
- Whitehead Institute for Biomedical Research, Department of Biology, MIT Ludwig Center for Molecular Oncology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Elizabeth D Williams
- Australian Prostate Cancer Research Centre-Queensland (APCRC-Q) and Queensland Bladder Cancer Initiative (QBCI), School of Biomedical Sciences and Institute of Health and Biomedical Innovation, Queensland University of Technology, Woolloongabba, QLD, Australia
| | - Jianhua Xing
- Department of Computational and Systems Biology and UPMC-Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Binhua P Zhou
- Department of Molecular and Cellular Biochemistry and UK Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Guojun Sheng
- International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan.
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Abstract
Renal fibrosis is a hallmark of chronic kidney disease. Although considerable achievements in the pathogenesis of renal fibrosis have been made, the underlying mechanisms of renal fibrosis remain largely to be explored. Now we have reached the consensus that TGF-β is a master regulator of renal fibrosis. Indeed, TGF-β regulates renal fibrosis via both canonical and noncanonical TGF-β signaling. Moreover, ongoing renal inflammation promotes fibrosis as inflammatory cells such as macrophages, conventional T cells and mucosal-associated invariant T cells may directly or indirectly contribute to renal fibrosis, which is also tightly regulated by TGF-β. However, anti-TGF-β treatment for renal fibrosis remains ineffective and nonspecific. Thus, research into mechanisms and treatment of renal fibrosis remains highly challenging.
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18
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Fu H, Gu YH, Yang YN, Liao S, Wang GH. MiR-200b/c family inhibits renal fibrosis through modulating epithelial-to-mesenchymal transition via targeting fascin-1/CD44 axis. Life Sci 2020; 252:117589. [PMID: 32220622 DOI: 10.1016/j.lfs.2020.117589] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 03/23/2020] [Accepted: 03/23/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND Renal fibrosis is the characteristic of all kinds of chronic kidney diseases (CKDs). Fascin-1 plays an important role in tumor development, but the roles of fascin-1 in renal fibrosis have not been studied. Here, we explored the role of fascin-1 in renal fibrosis and the potential mechanisms. METHODS Kidney unilateral ureteral obstruction (UUO) mouse model was used as an in vivo model, and proximal tubule epithelial cell lines treated with TGF-β1 were used as in vitro model of renal fibrosis. Cell transfection was performed to manipulate the expression of miR-200b/c, fascin-1 and CD44. Western blotting, qRT-PCR, immunohistochemistry or immunofluorescence assays were used to measure levels of miR-200b/c, fascin-1, CD44, and fibrosis and EMT-related markers. H&E and Masson stainings were used to examine the degree of injury and fibrosis in kidneys. Dual luciferase assay was used to examine the interaction between miR-200b/c family and fascin-1. RESULTS Fascin-1 and CD44 levels were both significantly up-regulated while miR-200b/c family was reduced in models of renal fibrosis. Furthermore, overexpression of miR-200b/c family and inhibition of fascin-1 or CD44 ameliorated renal fibrosis through suppressing EMT process. Mechanistically, miR-200b/c family directly and negatively regulated the expression of fascin-1. Overexpression of fascin-1 could reverse the effects of miR-200b/c family on renal fibrosis, and fascin-1 regulated renal fibrosis by activating CD44. CONCLUSION Our study is the first to show that fascin-1 plays a critical role in renal fibrosis. MiR-200b/c family could inhibit renal fibrosis through modulating EMT process by directly targeting fascin-1/CD44 axis.
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Affiliation(s)
- Hua Fu
- Department of Pathology, Third Xiangya Hospital, Central South University, Changsha 410013, PR China
| | - Yong-Hong Gu
- Department of Pathology, Third Xiangya Hospital, Central South University, Changsha 410013, PR China
| | - Ye-Ning Yang
- Department of Pathology, Third Xiangya Hospital, Central South University, Changsha 410013, PR China
| | - Shan Liao
- Department of Pathology, Third Xiangya Hospital, Central South University, Changsha 410013, PR China
| | - Guo-Hui Wang
- Medical Laboratory Center, Third Xiangya Hospital, Central South University, Changsha 410013, PR China.
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19
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Lindoso RS, Lopes JA, Binato R, Abdelhay E, Takiya CM, Miranda KRD, Lara LS, Viola A, Bussolati B, Vieyra A, Collino F. Adipose Mesenchymal Cells-Derived EVs Alleviate DOCA-Salt-Induced Hypertension by Promoting Cardio-Renal Protection. Mol Ther Methods Clin Dev 2020; 16:63-77. [PMID: 31871958 PMCID: PMC6909095 DOI: 10.1016/j.omtm.2019.11.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 11/02/2019] [Indexed: 12/20/2022]
Abstract
Hypertension is a long-term condition that can increase organ susceptibility to insults and lead to severe complications such as chronic kidney disease (CKD). Extracellular vesicles (EVs) are cell-derived membrane structures that participate in cell-cell communication by exporting encapsulated molecules to target cells, regulating physiological and pathological processes. We here demonstrate that multiple administration of EVs from adipose-derived mesenchymal stromal cells (ASC-EVs) in deoxycorticosterone acetate (DOCA)-salt hypertensive model can protect renal tissue by maintaining its filtration capacity. Indeed, ASC-EVs downregulated the pro-inflammatory molecules monocyte chemoattracting protein-1 (MCP-1) and plasminogen activating inhibitor-1 (PAI1) and reduced recruitment of macrophages in the kidney. Moreover, ASC-EVs prevented cardiac tissue fibrosis and maintained blood pressure within normal levels, thus demonstrating their multiple favorable effects in different organs. By applying microRNA (miRNA) microarray profile of the kidney of DOCA-salt rats, we identified a selective miRNA signature associated with epithelial-mesenchymal transition (EMT). One of the key pathways found was the axis miR-200-TGF-β, that was significantly altered by EV administration, thereby affecting the EMT signaling and preventing renal inflammatory response and fibrosis development. Our results indicate that EVs can be a potent therapeutic tool for the treatment of hypertension-induced CKD in cardio-renal syndrome.
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Affiliation(s)
- Rafael Soares Lindoso
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil
- National Center for Structural Biology and Bioimaging/CENABIO, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil
- National Institute of Science and Technology for Regenerative Medicine-REGENERA, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil
| | - Jarlene Alécia Lopes
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil
- National Center for Structural Biology and Bioimaging/CENABIO, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil
| | - Renata Binato
- Brazilian National Institute of Cancer, 20230-130 Rio de Janeiro, Brazil
| | - Eliana Abdelhay
- Brazilian National Institute of Cancer, 20230-130 Rio de Janeiro, Brazil
| | - Christina Maeda Takiya
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil
| | - Kildare Rocha de Miranda
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil
- National Center for Structural Biology and Bioimaging/CENABIO, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil
| | - Lucienne Silva Lara
- Institute of Biomedical Sciences, Federal University of Rio de Janeiro, 21941-590 Rio de Janeiro, Brazil
| | - Antonella Viola
- Department of Biomedical Sciences and Pediatric Research Institute “Citta della Speranza,” University of Padova, 35131 Padua, Italy
| | - Benedetta Bussolati
- Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Turin, Italy
| | - Adalberto Vieyra
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil
- National Center for Structural Biology and Bioimaging/CENABIO, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil
- National Institute of Science and Technology for Regenerative Medicine-REGENERA, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil
- Graduate Program of Translational Biomedicine/BIOTRANS, Grande Rio University, 25071-202 Duque de Caxias, Brazil
| | - Federica Collino
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil
- National Institute of Science and Technology for Regenerative Medicine-REGENERA, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil
- Department of Biomedical Sciences and Pediatric Research Institute “Citta della Speranza,” University of Padova, 35131 Padua, Italy
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20
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Gu YY, Liu XS, Huang XR, Yu XQ, Lan HY. Diverse Role of TGF-β in Kidney Disease. Front Cell Dev Biol 2020; 8:123. [PMID: 32258028 PMCID: PMC7093020 DOI: 10.3389/fcell.2020.00123] [Citation(s) in RCA: 153] [Impact Index Per Article: 30.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 02/12/2020] [Indexed: 12/13/2022] Open
Abstract
Inflammation and fibrosis are two pathological features of chronic kidney disease (CKD). Transforming growth factor-β (TGF-β) has been long considered as a key mediator of renal fibrosis. In addition, TGF-β also acts as a potent anti-inflammatory cytokine that negatively regulates renal inflammation. Thus, blockade of TGF-β inhibits renal fibrosis while promoting inflammation, revealing a diverse role for TGF-β in CKD. It is now well documented that TGF-β1 activates its downstream signaling molecules such as Smad3 and Smad3-dependent non-coding RNAs to transcriptionally and differentially regulate renal inflammation and fibrosis, which is negatively regulated by Smad7. Therefore, treatments by rebalancing Smad3/Smad7 signaling or by specifically targeting Smad3-dependent non-coding RNAs that regulate renal fibrosis or inflammation could be a better therapeutic approach. In this review, the paradoxical functions and underlying mechanisms by which TGF-β1 regulates in renal inflammation and fibrosis are discussed and novel therapeutic strategies for kidney disease by targeting downstream TGF-β/Smad signaling and transcriptomes are highlighted.
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Affiliation(s)
- Yue-Yu Gu
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Department of Nephrology, 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
| | - Xu-Sheng Liu
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Department of Nephrology, 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 Immunity and Genetics of Chronic Kidney Disease, Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, Guangzhou, China
| | - Xue-Qing Yu
- Guangdong-Hong Kong Joint Laboratory for Immunity and Genetics of Chronic Kidney Disease, Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, 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 Immunity and Genetics of Chronic Kidney Disease, Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, Guangzhou, China
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21
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Fierro-Fernández M, Miguel V, Márquez-Expósito L, Nuevo-Tapioles C, Herrero JI, Blanco-Ruiz E, Tituaña J, Castillo C, Cannata P, Monsalve M, Ruiz-Ortega M, Ramos R, Lamas S. MiR-9-5p protects from kidney fibrosis by metabolic reprogramming. FASEB J 2019; 34:410-431. [PMID: 31914684 DOI: 10.1096/fj.201901599rr] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 10/04/2019] [Accepted: 10/08/2019] [Indexed: 12/12/2022]
Abstract
MicroRNAs (miRNAs) regulate gene expression posttranscriptionally and control biological processes (BPs), including fibrogenesis. Kidney fibrosis remains a clinical challenge and miRNAs may represent a valid therapeutic avenue. We show that miR-9-5p protected from renal fibrosis in the mouse model of unilateral ureteral obstruction (UUO). This was reflected in reduced expression of pro-fibrotic markers, decreased number of infiltrating monocytes/macrophages, and diminished tubular epithelial cell injury and transforming growth factor-beta 1 (TGF-β1)-dependent de-differentiation in human kidney proximal tubular (HKC-8) cells. RNA-sequencing (RNA-Seq) studies in the UUO model revealed that treatment with miR-9-5p prevented the downregulation of genes related to key metabolic pathways, including mitochondrial function, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and glycolysis. Studies in human tubular epithelial cells demonstrated that miR-9-5p impeded TGF-β1-induced bioenergetics derangement. The expression of the FAO-related axis peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α)-peroxisome proliferator-activated receptor alpha (PPARα) was reduced by UUO, although preserved by the administration of miR-9-5p. We found that in mice null for the mitochondrial master regulator PGC-1α, miR-9-5p was unable to promote a protective effect in the UUO model. We propose that miR-9-5p elicits a protective response to chronic kidney injury and renal fibrosis by inducing reprogramming of the metabolic derangement and mitochondrial dysfunction affecting tubular epithelial cells.
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Affiliation(s)
- Marta Fierro-Fernández
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Madrid, Spain
| | - Verónica Miguel
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Madrid, Spain
| | | | - Cristina Nuevo-Tapioles
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Madrid, Spain
| | - J Ignacio Herrero
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Madrid, Spain
| | - Eva Blanco-Ruiz
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Madrid, Spain
| | - Jessica Tituaña
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Madrid, Spain
| | | | - Pablo Cannata
- Instituto de Investigación Sanitaria, Fundación Jiménez Díaz (UAM), Madrid, Spain
| | - María Monsalve
- Instituto de Investigaciones Biomédicas "Alberto Sols", (CSIC-UAM), Madrid, Spain
| | - Marta Ruiz-Ortega
- Instituto de Investigación Sanitaria, Fundación Jiménez Díaz (UAM), Madrid, Spain
| | - Ricardo Ramos
- Servicio de Genómica, Fundación Parque Científico de Madrid, Madrid, Spain
| | - Santiago Lamas
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Madrid, Spain
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22
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Yu J, Yu C, Feng B, Zhan X, Luo N, Yu X, Zhou Q. Intrarenal microRNA signature related to the fibrosis process in chronic kidney disease: identification and functional validation of key miRNAs. BMC Nephrol 2019; 20:336. [PMID: 31455266 PMCID: PMC6712721 DOI: 10.1186/s12882-019-1512-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 08/02/2019] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Though the roles of microRNAs (miRNAs) in renal diseases have been extensively investigated, a thorough screening and comparison of miRNAs among different types of chronic kidney disease (CKD) has never been performed. METHODS The intrarenal miRNAs were profiled from fresh kidney tissues of patients with biopsy-proven minimal change disease (MCD), focal segmental glomerular sclerosis (FSGS) and diabetic nephropathy (DN) by using microarray. Commonly dysregulated miRNAs were validated by real-time PCR using paraffin-embedded renal tissues from all three types of CKD patients as well as mouse unilateral ureteral obstruction (UUO) model. Two novel miRNAs were selected and annotations of their target genes were performed using GO and KEGG pathway enrichment analysis. Biological functions of three two candidate miRNAs were explored in TGF-β1-induced cell model using human kidney proximal tubular cells (HK-2). RESULTS The kidney biopsy samples of three disease types represent different levels of damage and fibrosis, which were the mildest in MCD, moderate in FSGS, and the most severe in DN. 116 miRNAs were identified to be commonly dysregulated, including 40 up-regulated and 76 down-regulated in CKD tissues as compared with healthy donor kidney biopsy tissues. Two novel miRNAs, hsa-miR-3607-3p and hsa-miR-4709-3p, were verified as consistently differentially expressed among all three types of patient samples as well as in mouse model. In vitro, hsa-miR-3607-3p was repressed while hsa-miR-4709-3p was induced by TGF-β1 treatment. Inhibition of hsa-miR-3607-3p or overexpression of hsa-miR-4709-3p promoted TGF-β1-induced migration and F-actin assembling in HK-2 cells, which are characteristics of epithelial-mesenchymal transition (EMT). Further study identified that ITGB8 and CALM3 were the bona fide target genes of hsa-miR-3607-3p and hsa-miR-4709-3p respectively. CONCLUSIONS The present identify a unique miRNAs profile that probably relates to the common fibrosis process of CKD. Results of our study suggest that hsa-miR-3607-3p and hsa-miR-4709-3p may represent as promising therapeutic targets against kidney fibrosis.
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Affiliation(s)
- Jianwen Yu
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, 58th, Zhongshan Road II, Guangzhou, China.,National Health Commission Key Laboratory of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Chaolun Yu
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Boya Feng
- Translational Medical Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaojiang Zhan
- Department of Nephrology, The First Affiliated Hospital, Nanchang University, Nanchang, China
| | - Ning Luo
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, 58th, Zhongshan Road II, Guangzhou, China.,National Health Commission Key Laboratory of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xueqing Yu
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, 58th, Zhongshan Road II, Guangzhou, China.,National Health Commission Key Laboratory of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong General Hospital, Guangzhou, China
| | - Qin Zhou
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, 58th, Zhongshan Road II, Guangzhou, China. .,National Health Commission Key Laboratory of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. .,Guangdong Provincial Key Laboratory of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
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23
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Srivastava SP, Hedayat AF, Kanasaki K, Goodwin JE. microRNA Crosstalk Influences Epithelial-to-Mesenchymal, Endothelial-to-Mesenchymal, and Macrophage-to-Mesenchymal Transitions in the Kidney. Front Pharmacol 2019; 10:904. [PMID: 31474862 PMCID: PMC6707424 DOI: 10.3389/fphar.2019.00904] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 07/18/2019] [Indexed: 12/20/2022] Open
Abstract
microRNAs (miRNAs) are small, non-coding nucleotides that regulate diverse biological processes. Altered microRNA biosynthesis or regulation contributes to pathological processes including kidney fibrosis. Kidney fibrosis is characterized by deposition of excess extracellular matrix (ECM), which is caused by infiltration of immune cells, inflammatory cells, altered chemokines, and cytokines as well as activation and accumulation of fibroblasts in the kidney. These activated fibroblasts can arise from epithelial cells via epithelial-to-mesenchymal transition (EMT), from bone marrow-derived M2 phenotype macrophages via macrophage-to-mesenchymal transition (MMT), from endothelial cells via endothelial-to-mesenchymal transition (EndMT), from resident fibroblasts, and from bone marrow-derived monocytes and play a crucial role in fibrotic events. Disrupted microRNA biosynthesis and aberrant regulation contribute to the activation of mesenchymal programs in the kidney. miR-29 regulates the interaction between dipeptidyl peptidase-4 (DPP-4) and integrin β1 and the associated active transforming growth factor β (TGFβ) and pro-EndMT signaling; however, miR-let-7 targets transforming growth factor β receptors (TGFβRs) to inhibit TGFβ signaling. N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is an endogenous anti-fibrotic peptide, which is associated with fibroblast growth factor receptor 1 (FGFR1) phosphorylation and subsequently responsible for the production of miR-let-7. miR-29 and miR-let-7 family clusters participate in crosstalk mechanisms, which are crucial for endothelial cell homeostasis. The physiological level of AcSDKP is vital for the activation of anti-fibrotic mechanisms including restoration of anti-fibrotic microRNA crosstalk and suppression of profibrotic signaling by mitigating DPP-4-associated mesenchymal activation in the epithelial cells, endothelial cells, and M2 phenotype macrophages. The present review highlights recent advancements in the understanding of both the role of microRNAs in the development of kidney disease and their potential as novel therapeutic targets for fibrotic disease states.
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Affiliation(s)
| | - Ahmad Fahim Hedayat
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT, United States
| | - Keizo Kanasaki
- Internal Medicine 1, Shimane University Faculty of Medicine, Izumo, Japan
| | - Julie E Goodwin
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT, United States
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24
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Yang SX, Zhang ZC, Bai HL. ClC-5 alleviates renal fibrosis in unilateral ureteral obstruction mice. Hum Cell 2019; 32:297-305. [PMID: 31054069 DOI: 10.1007/s13577-019-00253-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 04/10/2019] [Indexed: 02/07/2023]
Abstract
Renal fibrosis is the major feature of end-stage renal disease with high mortality. Chloride (Cl-) moving along Cl- channels has been suggested to play to an important role in renal function. This study aims to investigate the role of ClC-5 in renal fibrosis in unilateral ureteral occlusion (UUO) mice. C57BL/6 mice received UUO surgery followed by delivery of adeno-associated virus encoding ClC-5 cDNA (AAVClC-5). Western blotting, real-time PCR and histological analysis were used to investigate the effects of ClC-5 on renal fibrosis and underlying mechanisms. The expression of ClC-5 was significantly decreased in renal cortex of UUO mice and transforming growth factor-β1 (TGF-β1)-stimulated HK2 cells. Overexpression of ClC-5 in vivo markedly ameliorated UUO-induced renal injury and fibrosis. The increased expressions of plasminogen activator inhibitor type 1, connective tissue growth factor, collagen III and collagen IV were also inhibited by ClC-5 upregulation. Moreover, UUO-induced immune cell infiltration and inflammatory cytokines release were attenuated in mice infected with AAVClC-5. In addition, the in vivo and in vitro results showed that ClC-5 overexpression prevented epithelial-to-mesenchymal transition (EMT), concomitantly with a restoration of E-cadherin expression and a decrease of vimentin, α-SMA and S100A4 expressions. Furthermore, ClC-5 overexpression inhibited UUO- or TGF-β1-induced increase in nuclear factor kappa B (NF-κB) acetylation and matrix metalloproteinases-9 (MMP-9) expression. However, downregulation of ClC-5 in HK2 cells further potentiated TGF-β1-induced EMT and increase in NF-κB acetylation and MMP-9 expression. ClC-5 upregulation ameliorates renal fibrosis via inhibiting NF-κB/MMP-9 pathway signaling activation, suggesting that ClC-5 may be a novel therapeutic target for treating renal fibrosis and chronic kidney disease.
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Affiliation(s)
- Shi-Xia Yang
- Department of Nephrology, Gansu Provincial Hospital of Traditional Chinese Medicine, No. 418 Guazhou Road, Lanzhou, 730050, Gansu, China.
| | - Zheng-Chang Zhang
- Department of Neurology, Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, China
| | - Hui-Ling Bai
- Department of Nephrology, Gansu Provincial Hospital of Traditional Chinese Medicine, No. 418 Guazhou Road, Lanzhou, 730050, Gansu, China
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25
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Non-Coding RNAs as New Therapeutic Targets in the Context of Renal Fibrosis. Int J Mol Sci 2019; 20:ijms20081977. [PMID: 31018516 PMCID: PMC6515288 DOI: 10.3390/ijms20081977] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 04/19/2019] [Accepted: 04/20/2019] [Indexed: 12/15/2022] Open
Abstract
Fibrosis, or tissue scarring, is defined as the excessive, persistent and destructive accumulation of extracellular matrix components in response to chronic tissue injury. Renal fibrosis represents the final stage of most chronic kidney diseases and contributes to the progressive and irreversible decline in kidney function. Limited therapeutic options are available and the molecular mechanisms governing the renal fibrosis process are complex and remain poorly understood. Recently, the role of non-coding RNAs, and in particular microRNAs (miRNAs), has been described in kidney fibrosis. Seminal studies have highlighted their potential importance as new therapeutic targets and innovative diagnostic and/or prognostic biomarkers. This review will summarize recent scientific advances and will discuss potential clinical applications as well as future research directions.
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26
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A Glimpse of the Mechanisms Related to Renal Fibrosis in Diabetic Nephropathy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1165:49-79. [PMID: 31399961 DOI: 10.1007/978-981-13-8871-2_4] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Diabetic nephropathy (DN) is a common kidney disease in people with diabetes, which is also a serious microvascular complication of diabetes and the main cause of end-stage renal disease (ESRD) in developed and developing countries. Renal fibrosis is a finally pathological change in DN. Nevertheless, the relevant mechanism of cause to renal fibrosis in DN is still complex. In this review, we summarized that the role of cell growth factors, epithelial-mesenchymal transition (EMT) in the renal fibrosis of DN, we also highlighted the miRNA and inflammatory cells, such as macrophage, T lymphocyte, and mastocyte modulate the progression of DN. In addition, there are certain other mechanisms that may yet be conclusively defined. Recent studies demonstrated that some of the new signaling pathways or molecules, such as Notch, Wnt, mTOR, Epac-Rap-1 pathway, may play a pivotal role in the modulation of ECM accumulation and renal fibrosis in DN. This review aims to elucidate the mechanism of renal fibrosis in DN and has provided new insights into possible therapeutic interventions to inhibit renal fibrosis and delay the development of DN.
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27
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Alkandari A, Ashrafian H, Sathyapalan T, Darzi A, Holmes E, Athanasiou T, Atkin SL, Gooderham NJ. Bariatric Surgery Modulates Urinary Levels of MicroRNAs Involved in the Regulation of Renal Function. Front Endocrinol (Lausanne) 2019; 10:319. [PMID: 31164867 PMCID: PMC6536704 DOI: 10.3389/fendo.2019.00319] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Accepted: 05/02/2019] [Indexed: 12/14/2022] Open
Abstract
Background: Obesity and diabetes cause chronic kidney disease with a common pathophysiology that is characterized by the accumulation of collagen in the extracellular matrix. Recent evidence has implicated the epithelial-to-mesenchymal transition (EMT) as a key step in this pathology with regulation by microRNAs. Weight loss leads to improvements in renal function; therefore, this study hypothesized that bariatric-surgery aided weight loss would lead to changes in urinary microRNAs involved in the regulation of renal function. Materials and methods: Twenty-four bariatric patients undergoing Roux-en-Y gastric bypass and sleeve gastrectomy donated urine pre-operatively and at 2-6 months and 1-2 years post-operatively. Urine samples were also obtained from 10 healthy weight and 7 morbidly obese non-surgical controls. Expression levels of kidney microRNAs were assessed in urine and the function of microRNAs was assessed through the in vitro transfection of HK-2 cells, a kidney proximal tubule cell line. Results: Levels of miR 192, miR 200a, and miR 200b were upregulated in urine following bariatric surgery. This increase was consistent across surgical type and diabetes status and was maintained and enhanced with time. Bariatric surgery alters urinary miR 192 expression from levels seen in morbidly obese patients to levels seen in healthy weight control patients. In mechanistic studies, the transfection of miR 192 in HK-2 cells increased miR 200a expression and decreased ZEB2, a key transcriptional promoter of kidney fibrosis. Conclusions: Bariatric surgery increased miR 192 and miR 200 urinary levels, key anti-fibrotic microRNAs that could contribute to a renal-protective mechanism and may be of value as urinary biomarkers following surgery. These findings suggest that urinary microRNAs may represent potential novel biomarkers for obesity-associated renal function.
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Affiliation(s)
- Abdullah Alkandari
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
- Dasman Diabetes Institute, Kuwait City, Kuwait
- *Correspondence: Abdullah Alkandari
| | - Hutan Ashrafian
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
- Institute of Global Health Innovation, Imperial College London, London, United Kingdom
| | - Thozhukat Sathyapalan
- Department of Academic Endocrinology, Diabetes, and Metabolism, Hull York Medical School, Kingston upon Hull, United Kingdom
| | - Ara Darzi
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
- Institute of Global Health Innovation, Imperial College London, London, United Kingdom
| | - Elaine Holmes
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Thanos Athanasiou
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Stephen L. Atkin
- Weill Cornell Medical College Qatar, Qatar Foundation, Doha, Qatar
| | - Nigel J. Gooderham
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
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28
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Xi W, Zhao X, Wu M, Jia W, Li H. Lack of microRNA-155 ameliorates renal fibrosis by targeting PDE3A/TGF-β1/Smad signaling in mice with obstructive nephropathy. Cell Biol Int 2018; 42:1523-1532. [PMID: 30080287 DOI: 10.1002/cbin.11038] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 07/29/2018] [Indexed: 11/06/2022]
Abstract
Although microRNA-155 (miR-155) is implicated in the pathogenesis of several fibrotic diseases, information regarding its functional role in renal fibrosis is limited. The current study aims to investigate the effects of miR-155 on renal fibrosis in unilateral ureteral occlusion (UUO) mice. MiR-155 level was significantly increased in renal tissues of UUO mice and TGF-β1-treated HK2 cells. Masson's trichrome staining showed that delivery of adeno-associated virus encoding miR-155 inhibitor led to a decrease in renal fibrosis induced by UUO. The increased expression of plasminogen activator inhibitor type 1, collagen III and collagen IV was also inhibited after miR-155 inhibition. In addition, miR-155 knockdown also prevented TGF-β1-induced epithelial-mesenchymal transition, concomitantly with a restoration of E-cadherin expression and a decrease of vimentin expression. Computational analysis revealed that miR-155 directly targets at 3'UTR of PDE3A. Overexpression of miR-155 suppressed the luciferase activity and protein expression of PDE3A, whereas inhibition of miR-155 increased PDE3A luciferase activity and expression. Furthermore, miR-155 inhibited TGF-β1-induced the increase of TGF-β1 expression and Smad-2/3 phosphorylation in HK2 cells. In contrast, knockdown of PDE3A reversed the effect of miR-155 inhibition on TGF-β1 expression. This study demonstrates that knockdown of miR-155 attenuates renal fibrosis via inhibiting TGF-β1/Smad signaling activation by targeting the upstream molecule PDE3A. This study suggests that miR-155 inhibition may be a novel therapeutic approach for preventing fibrotic kidney diseases.
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Affiliation(s)
- Weiwei Xi
- Department of Nephrology, Zhejiang University Medical College Affiliated Sir Run Run Shaw Hospital, Qingchun Road 3rd, Hangzhou 310016, Zhejiang Province, China
| | - Xuming Zhao
- Department of Nephrology, Zhejiang University Medical College Affiliated Sir Run Run Shaw Hospital, Qingchun Road 3rd, Hangzhou 310016, Zhejiang Province, China
| | - Meijun Wu
- Department of Comprehensive Health Care, The First People's Hospital of Hangzhou, Hangzhou 310016, Zhejiang Province, China
| | - Wenjuan Jia
- Department of Nephrology, Zhejiang University Medical College Affiliated Sir Run Run Shaw Hospital, Qingchun Road 3rd, Hangzhou 310016, Zhejiang Province, China
| | - Hua Li
- Department of Nephrology, Zhejiang University Medical College Affiliated Sir Run Run Shaw Hospital, Qingchun Road 3rd, Hangzhou 310016, Zhejiang Province, China
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29
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Lu MY, Yu CC, Chen PY, Hsieh PL, Peng CY, Liao YW, Yu CH, Lin KH. miR-200c inhibits the arecoline-associated myofibroblastic transdifferentiation in buccal mucosal fibroblasts. J Formos Med Assoc 2018; 117:791-797. [PMID: 29958727 DOI: 10.1016/j.jfma.2018.05.016] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2018] [Revised: 05/11/2018] [Accepted: 05/24/2018] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND/PURPOSE MicroRNA-200c (miR-200c) recently emerged as an important regulator of tumorigenesis and cancer metastasis, however, its role in regulating oral submucous fibrosis (OSF) remains unknown. In this study, we investigated the functional role of miR-200c in myofibroblastic differentiation activity and identified its potential target. METHODS qRT-PCR was applied to assess the expression of miR-200c in OSF tissues and fibrotic buccal mucosal fibroblasts (fBMFs). Arecoline, a major areca nut alkaloid, was utilized to explore whether the expression of miR-200c would alter following stimulation. Collagen gel contraction, migration and invasion capabilities were examined in arecoline-stimulated BMFs as wells as in fBMFs. Luciferase reporter assay was conducted to show the relationship between miR-200c and ZEB1. RESULTS Our results showed that the expression of miR-200c was downregulated in OSF specimen and fBMFs. Arecoline treatment dose-dependently reduced the relative expression of miR-200c in normal BMFs. Overexpression of miR-200c impeded the arecoline-induced collagen gel contraction, migration, invasion and wound healing capacities. Moreover, ectopic expression of miR-200c in fBMFs successfully reduced the increased collagen gel contractility and invasion abilities. Our results demonstrated that ZEB1 was a direct target of miR-200c, and overexpression of miR-200c inhibited the expression of ZEB1 and α-SMA. CONCLUSION These findings suggest that downregulation of miR-200c in OSF may be involved in the pathogenesis of areca nut-associated OSF through regulation of ZEB1.
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Affiliation(s)
- Ming-Yi Lu
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan; Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Cheng-Chia Yu
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan; Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan; Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
| | - Pei-Yin Chen
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan; Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Pei-Ling Hsieh
- Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
| | - Chih-Yu Peng
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan; Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Yi-Wen Liao
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
| | - Chuan-Hang Yu
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan; Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan.
| | - Kuo-Hua Lin
- Department of General Surgery, Changhua Christian Hospital, Changhua, Taiwan.
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30
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Liao YW, Yu CC, Hsieh PL, Chang YC. miR-200b ameliorates myofibroblast transdifferentiation in precancerous oral submucous fibrosis through targeting ZEB2. J Cell Mol Med 2018; 22:4130-4138. [PMID: 29893466 PMCID: PMC6111815 DOI: 10.1111/jcmm.13690] [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: 10/02/2017] [Accepted: 04/20/2018] [Indexed: 12/28/2022] Open
Abstract
Oral submucous fibrosis (OSF) is a progressive scarring disease. MicroRNA-200b (miR-200b) has been reported as a tumour suppressor, but its role in the precancerous OSF remains unknown. In this study, we investigated the impact of miR-200b on myofibroblastic differentiation activity. Arecoline is a major areca nut alkaloid and has been employed to induce the elevated myofibroblast activity in human buccal mucosal fibroblasts (BMFs). Treatment of arecoline in BMFs dose-dependently reduced gene expression of miR-200b, which corresponded with the decreased expression of miR-200b in fBMFs. The arecoline-induced myofibroblast activities were abolished by overexpression of miR-200b in BMFs, and the same results were observed in fBMFs. In addition, α-SMA was inhibited by an increase in miR-200b. We further demonstrated that miR-200b-mediated decrease in ZEB2 led to down-regulation of α-SMA, vimentin. Loss of miR-200b resulted in enhanced collagen contraction and migration capabilities, and knockdown of ZEB2 reversed these phenomena. Lastly, we showed the expression of miR-200b was significantly less and ZEB2 was markedly higher in OSF tissues. These results suggested that down-regulation of miR-200b may contribute to the pathogenesis of areca quid-associated OSF through the regulation of ZEB2 and myofibroblast hallmarks.
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Affiliation(s)
- Yi-Wen Liao
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
| | - Cheng-Chia Yu
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan.,Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
| | - Pei-Ling Hsieh
- Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
| | - Yu-Chao Chang
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan.,Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
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31
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Yang H, Liao D, Tong L, Zhong L, Wu K. MiR-373 exacerbates renal injury and fibrosis via NF-κB/MatrixMetalloproteinase-9 signaling by targeting Sirtuin1. Genomics 2018; 111:786-792. [PMID: 29723660 DOI: 10.1016/j.ygeno.2018.04.017] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Revised: 04/24/2018] [Accepted: 04/29/2018] [Indexed: 12/19/2022]
Abstract
BACKGROUND Renal fibrosis is a final common pathway of chronic kidney disease. SIRT1, a NAD+-dependent protein deacetylase, deacetylates the p65 of NF-κB and shows protective effects in kidney disorders. miR-373 directly targets the 3'UTR of SIRT1. However, roles of miR-373 in renal fibrosis are unclear. METHODS TGF-β1, a critical regulator of fibrosis, was used to stimulate human kidney-2 cells to establish cell model for renal fibrosis. Unilateral ureteral obstruction (UUO) was performed as an in vivo model. RESULTS TGF-β1 induced the level of miR-373, reduced level of SIRT1, and promoted p65 acetylation and MMP-9 expression. These effects were reversed by the miR-373 inhibitor. In the animal model, UUO caused a consistent pattern as demonstrated in vitro. CONCLUSION These results indicated an undesired effect of miR-373 in the regulation of renal injury and fibrosis by targeting SIRT1-mediated NF-κB/MMP-9 signaling, which might provide a potential therapeutic strategy for renal fibrosis.
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Affiliation(s)
- Huihui Yang
- Department of Nephrology, The Third Xiangya Hospital of Central South University, Changsha 410013, PR China
| | - Dongmei Liao
- Department of Nephrology, The Third Xiangya Hospital of Central South University, Changsha 410013, PR China
| | - Liang Tong
- Department of Nephrology, The Third Xiangya Hospital of Central South University, Changsha 410013, PR China
| | - Ling Zhong
- Department of Nephrology, The Third Xiangya Hospital of Central South University, Changsha 410013, PR China
| | - Kun Wu
- Department of Nephrology, The Third Xiangya Hospital of Central South University, Changsha 410013, PR China.
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32
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Zhang C, Liang S, Cheng S, Li W, Wang X, Zheng C, Zeng C, Shi S, Xie L, Zen K, Liu Z. Urinary miR-196a predicts disease progression in patients with chronic kidney disease. J Transl Med 2018; 16:91. [PMID: 29636065 PMCID: PMC5894160 DOI: 10.1186/s12967-018-1470-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 04/02/2018] [Indexed: 11/13/2022] Open
Abstract
Background Urinary miRNAs may potentially serve as noninvasive biomarkers in various kidney diseases to reflect disease activity, severity and progression, especially those correlated with the pathogenesis of kidney diseases. This study demonstrates that urinary miR-196a, a kidney-enriched miRNA, can predict progression of chronic kidney disease (CKD). Methods Focal segmental glomerulosclerosis (FSGS) cohorts were used as the representative example of CKD. First, correlation of miR-196a with disease activity was analyzed using paired urine and plasma samples from FSGS patients with nephrotic-range proteinuria (FSGS-A), complete remission (FSGS-CR) and normal controls (NCs). Then, the value of urinary miR-196a in predicting disease progression was validated using another cohort of 231 FSGS patients who were followed-up until over 36 months or reaching end-stage renal disease (ESRD). MiR-196a levels were analyzed by quantitative reverse transcription-polymerase chain reaction. Results The results showed that urinary miR-196a significantly increased in FSGS-A compared with FSGS-CR and NCs, clearly distinguishing FSGS-A from FSGS-CR and NCs, whereas plasma miR-196a showed no difference among these groups. Moreover, urinary miR-196a, which was associated with proteinuria, estimated glomerular filtration rate (eGFR), interstitial fibrosis and tubular atrophy, significantly increased in patients progressed to ESRD compared to those not. Furthermore, patients with higher urinary miR-196a displayed poorer renal survival than those with lower urinary miR-196a. Multivariate Cox analysis confirmed urinary miR-196a as an independent risk factor for FSGS progression after adjusting for age, sex, proteinuria and eGFR. Prediction accuracy of ESRD was significantly improved by combining urinary miR-196a with other indicators including eGFR and proteinuria. Conclusion Urinary miR-196a may serve as a biomarker for predicting CKD progression Electronic supplementary material The online version of this article (10.1186/s12967-018-1470-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Changming Zhang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210002, Jiangsu, China
| | - Shaoshan Liang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210002, Jiangsu, China
| | - Shuiqin Cheng
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210002, Jiangsu, China
| | - Wei Li
- Shanghai Center for Bioinformation Research Technology, Shanghai Academy of Science and Technology, Shanghai, China
| | - Xia Wang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210002, Jiangsu, China
| | - Chunxia Zheng
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210002, Jiangsu, China
| | - Caihong Zeng
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210002, Jiangsu, China
| | - Shaolin Shi
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210002, Jiangsu, China
| | - Lu Xie
- Shanghai Center for Bioinformation Research Technology, Shanghai Academy of Science and Technology, Shanghai, China
| | - Ke Zen
- State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing University School of Life Sciences, Nanjing, 210093, Jiangsu, China.
| | - Zhihong Liu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210002, Jiangsu, China.
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Piperigkou Z, Götte M, Theocharis AD, Karamanos NK. Insights into the key roles of epigenetics in matrix macromolecules-associated wound healing. Adv Drug Deliv Rev 2018; 129:16-36. [PMID: 29079535 DOI: 10.1016/j.addr.2017.10.008] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 10/14/2017] [Accepted: 10/20/2017] [Indexed: 02/08/2023]
Abstract
Extracellular matrix (ECM) is a dynamic network of macromolecules, playing a regulatory role in cell functions, tissue regeneration and remodeling. Wound healing is a tissue repair process necessary for the maintenance of the functionality of tissues and organs. This highly orchestrated process is divided into four temporally overlapping phases, including hemostasis, inflammation, proliferation and tissue remodeling. The dynamic interplay between ECM and resident cells exerts its critical role in many aspects of wound healing, including cell proliferation, migration, differentiation, survival, matrix degradation and biosynthesis. Several epigenetic regulatory factors, such as the endogenous non-coding microRNAs (miRNAs), are the drivers of the wound healing response. microRNAs have pivotal roles in regulating ECM composition during wound healing and dermal regeneration. Their expression is associated with the distinct phases of wound healing and they serve as target biomarkers and targets for systematic regulation of wound repair. In this article we critically present the importance of epigenetics with particular emphasis on miRNAs regulating ECM components (i.e. glycoproteins, proteoglycans and matrix proteases) that are key players in wound healing. The clinical relevance of miRNA targeting as well as the delivery strategies designed for clinical applications are also presented and discussed.
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miR-200b/c attenuates lipopolysaccharide-induced early pulmonary fibrosis by targeting ZEB1/2 via p38 MAPK and TGF-β/smad3 signaling pathways. J Transl Med 2018; 98:339-359. [PMID: 29200203 DOI: 10.1038/labinvest.2017.123] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2017] [Revised: 09/03/2017] [Accepted: 09/21/2017] [Indexed: 12/26/2022] Open
Abstract
Pulmonary fibrosis triggered during the early stage of acute respiratory distress syndrome (ARDS) contributes to poor prognosis in patients. However, whether microRNAs (miRNAs) can serve as therapeutic targets for early pulmonary fibrosis during ARDS is still largely unknown. In this study, we evaluated the effects and mechanisms of miR-200s and its targets ZEB1/2 in lung tissue. An early pulmonary fibrosis mouse model caused by ARDS was established via a lipopolysaccharide (LPS) three-hit regimen. Lentiviral packaged miR-200b/c cDNA or ZEB1/2 shRNA was intratracheally administered into the lungs of C57BL/6 mice 1 day before an LPS injection was administered. In vitro, following a 30-min pretreatment with miR-200b/c or SB203580/SIS3, RLE-6TN cells were stimulated by LPS or LPS + transforming growth factor-β (TGF-β) for 24 h. miR-200b/c and E-cadherin protein expression declined, whereas ZEB1/2 mRNA and protein and vimentin and α-smooth muscle actin (α-SMA) protein levels gradually increased during the development of pulmonary fibrosis. Furthermore, both the overexpression of miR-200b/c and the silencing of ZEB1/2 significantly alleviated pulmonary inflammation and fibrosis, reduced vimentin and α-SMA expression, and increased E-cadherin protein levels. In RLE-6TN cells, LPS combined with TGF-β exerts synergistic effects of increasing vimentin and α-SMA protein levels, increasing p38 and smad3 phosphorylation and reducing E-cadherin protein levels, which were reversed by pretreatment with miR-200b/c or SB203580/SIS3. Our findings demonstrate that miR-200b/c was downregulated, whereas ZEB1/2 was upregulated in the development of LPS-induced early pulmonary fibrosis. miR-200b/c exerts a protective effect by targeting ZEB1/2, which may be associated with the inhibition of p38 MAPK and TGF-β /smad3 signaling pathways.
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Transforming Growth Factor-β and Bone Morphogenetic Protein 2 Regulation of MicroRNA-200 Family in Chronic Pancreatitis. Pancreas 2018; 47:252-256. [PMID: 29303912 PMCID: PMC5776736 DOI: 10.1097/mpa.0000000000000980] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVES To investigate regulation of microRNA (miR)-200 family (a, b, c, 141, and 429) in chronic pancreatitis (CP). This was accomplished by examining miR-200 family levels in a mouse model in vivo and their regulation in pancreatic cells in vitro. METHODS Chronic pancreatitis was induced by cerulein for 4 weeks (50 μg/kg, 5 hourly intraperitoneal injections/day, and 3 days/week). Control mice received normal saline. The pancreata were harvested for fibrosis assessment by Sirius red staining and for miRNA, collagen, and fibronectin levels by quantitative PCR. In vitro, human primary pancreatic stellate cells and human primary pancreatic fibroblast (hPFBs), and rat pancreatic epithelial AR42J cells were treated with vehicle, transforming growth factor (TGF)-β (1 ng/mL), or BMP2 (50 ng/mL) for 24 hours and then harvested for miRNA analysis. RESULTS In CP, miR-200s were decreased by 56% to 70% and inversely correlated with pancreatic fibrosis, miR-21, and miR-31 (P < 0.05). In vitro, TGF-β inhibited miR-200b in AR42J cells by 62%, whereas BMP2 increased miR-200b in all 3 cell types in a range of 1.5- to 3.4-fold and inhibited miR-21 in hPFBs by 21% (P < 0.05). CONCLUSIONS Both in vivo and in vitro studies suggest an antifibrogenic function of miR-200s in CP. The TGF-β and BMP2 may function through inverse regulation of miR-200b levels.
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Ning X, Zhang K, Wu Q, Liu M, Sun S. Emerging role of Twist1 in fibrotic diseases. J Cell Mol Med 2018; 22:1383-1391. [PMID: 29314610 PMCID: PMC5824384 DOI: 10.1111/jcmm.13465] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 10/20/2017] [Indexed: 01/04/2023] Open
Abstract
Epithelial–mesenchymal transition (EMT) is a pathological process that occurs in a variety of diseases, including organ fibrosis. Twist1, a basic helix–loop–helix transcription factor, is involved in EMT and plays significant roles in various fibrotic diseases. Suppression of the EMT process represents a promising approach for the treatment of fibrotic diseases. In this review, we discuss the roles and the underlying molecular mechanisms of Twist1 in fibrotic diseases, including those affecting kidney, lung, skin, oral submucosa and other tissues. We aim at providing new insight into the pathogenesis of various fibrotic diseases and facilitating the development of novel diagnostic and therapeutic methods for their treatment.
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Affiliation(s)
- Xiaoxuan Ning
- Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.,State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Kun Zhang
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Qingfeng Wu
- Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.,State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Minna Liu
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Shiren Sun
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
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37
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Ichii O, Horino T. MicroRNAs associated with the development of kidney diseases in humans and animals. J Toxicol Pathol 2018; 31:23-34. [PMID: 29479137 PMCID: PMC5820100 DOI: 10.1293/tox.2017-0051] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 09/10/2017] [Indexed: 12/20/2022] Open
Abstract
Mature microRNAs (miRNAs) are single-stranded RNAs with approximately 18-25 bases, and their sequences are highly conserved among animals. miRNAs act as posttranscriptional regulators by binding mRNAs, and their main function involves the degradation of their target mRNAs. Recent studies revealed altered expression of miRNAs in the kidneys during the progression of acute kidney injury (AKI) and chronic kidney disease (CKD) in humans and experimental rodent models by using high-throughput screening techniques including microarray and small RNA sequencing. Particularly, miR-21 seems to be strongly associated with renal pathogenesis both in the glomerulus and tubulointerstitium. Furthermore, abundant evidence has been gathered showing the involvement of miRNAs in renal fibrosis. Because of the complex morphofunctional organization of the mammalian kidneys, it is crucial both to determine the exact localization of the kidney cells that express the miRNAs, which has been addressed mainly using in situ hybridization methods, and to identify precisely which mRNAs are bound and degraded by these miRNAs, which has been studied mostly through in vitro analysis. To discover novel biomarker candidates, miRNA levels in urine supernatant, sediment, and exosomal fraction were comprehensively investigated in different types of kidney disease, including drug-induced AKI, ischemia-induced AKI, diabetic nephropathy, lupus nephritis, and IgA nephropathy. Recent studies also demonstrated the therapeutic effect of miRNA and/or anti-miRNA administrations. The intent of this review is to illustrate the state-of-the-art research in the field of miRNAs associated with renal pathogenesis, especially focusing on AKI and CKD in humans and animal models.
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Affiliation(s)
- Osamu Ichii
- Laboratory of Anatomy, Department of Basic Veterinary
Sciences, Faculty of Veterinary Medicine, Hokkaido University, Kita 18-Nishi 9, Kita-ku,
Sapporo, Hokkaido 060-0818, Japan
| | - Taro Horino
- Laboratory of Anatomy, Department of Basic Veterinary
Sciences, Faculty of Veterinary Medicine, Hokkaido University, Kita 18-Nishi 9, Kita-ku,
Sapporo, Hokkaido 060-0818, Japan
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38
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Lin H, Ewing LE, Koturbash I, Gurley BJ, Miousse IR. MicroRNAs as biomarkers for liver injury: Current knowledge, challenges and future prospects. Food Chem Toxicol 2017; 110:229-239. [PMID: 29042291 PMCID: PMC6693868 DOI: 10.1016/j.fct.2017.10.026] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 10/02/2017] [Accepted: 10/14/2017] [Indexed: 12/12/2022]
Abstract
MicroRNAs (miRNAs) are short regulatory RNAs that are involved in various biological processes that regulate gene expression posttranscriptionally. Changes in miRNA expression can be detected in many physiological and pathological events, such as liver injury. Drug induced liver injury is a life threatening condition that frequently requires organ transplantation. Hepatotoxicity is also one of the major causes of drug failure in clinical trials and of drug withdrawal from the market. The profiling of miRNA expression shows great promise in monitoring liver injury, in the prediction of outcome in patients, and in the identification of liver-reactive compounds in toxicological assessment. Recent studies have demonstrated organ-specificity of some miRNAs (i.e., miR-122), which are released into biological fluids as a result of hepatocyte damage. This attests to the potential of miRNAs as noninvasive biomarkers to detect liver toxicity. This review presents information on miRNA signatures of hepatotoxicity and on the application of promising miRNA biomarkers in preclinical safety assessment. We further discuss the technical challenges associated with these emerging biomarkers for early diagnosis and detection of hepatotoxicity.
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Affiliation(s)
- Haixia Lin
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, United States.
| | - Laura E Ewing
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, United States; Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, United States.
| | - Igor Koturbash
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, United States.
| | - Bill J Gurley
- Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, 72223, United States.
| | - Isabelle R Miousse
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, United States.
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Yang J, Zhou CZ, Zhu R, Fan H, Liu XX, Duan XY, Tang Q, Shou ZX, Zuo DM. miR-200b-containing microvesicles attenuate experimental colitis associated intestinal fibrosis by inhibiting epithelial-mesenchymal transition. J Gastroenterol Hepatol 2017; 32:1966-1974. [PMID: 28370348 DOI: 10.1111/jgh.13797] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2016] [Revised: 03/06/2017] [Accepted: 03/28/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Epithelial-mesenchymal transition (EMT), characterized by the decrease of E-cadherin (E-Cad) and increase in vimentin and alpha-smooth muscle actin (α-SMA), was demonstrated to participate in inflammatory bowel disease-related fibrosis. miR-200b plays an anti-fibrosis role in inhibiting EMT by targeting ZEB1 and ZEB2. But the stability of exogenous miR-200b in blood limits its application. Microvesicles (MVs), which can transfer miRNAs among cells and prevent them from degradation, may provide an excellent transport system for the delivery of miR-200b in the treatment of fibrosis. METHODS Bone marrow mesenchymal stem cells (BMSCs) were transfected with lentivirus to overexpress miR-200b. The MVs packaged with miRNA-200b were harvested for the anti-fibrotic treatment using in vitro (transforming growth factor beta 1-mediated EMT in intestinal epithelial cells: IEC-6) and in vivo (TNBS-induced intestinal fibrosis in rats) models. The pathological morphology was observed, and the fibrosis related proteins, such as E-Cad, vimentin, α-SMA, ZEB1, and ZEB2, were detected. RESULTS MiR-200b-MVs would significantly reverse the morphology in TGF-β1-treated IEC-6 cells and improve the TNBS-induced colon fibrosis histologically. The treatment of miR-200b-MVs increased miR-200b levels both in the IEC-6 cells and colon, resulting in a significant prevention EMT and alleviation of fibrosis. The expression of E-Cad was increased, and the expressions of vimentin and α-SMA were decreased. ZBE1 and ZEB2, the targets of miR-200b, were also decreased. CONCLUSIONS miR-200b could be transferred from genetically modified BMSCs to the target cells or tissue by MVs. The mechanisms of miR-200b-MVs in inhibiting colonic fibrosis were related to suppressing the development of EMT by targeting ZEB1and ZEB2.
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Affiliation(s)
- Jia Yang
- Department of Integrated Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cheng-Zhi Zhou
- Department of Integrated Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Cardiology, The Affiliated Hospital of Hubei University of Traditional Chinese Medicine, Wuhan, China
| | - Rui Zhu
- Department of Integrated Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Heng Fan
- Department of Integrated Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xing-Xing Liu
- Department of Integrated Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xue-Yun Duan
- Department of Pharmacy, The Affiliated Hospital of Hubei University of Traditional Chinese Medicine, Wuhan, China
| | - Qing Tang
- Department of Integrated Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhe-Xing Shou
- Department of Integrated Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dong-Mei Zuo
- Department of Integrated Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Lv W, Fan F, Wang Y, Gonzalez-Fernandez E, Wang C, Yang L, Booz GW, Roman RJ. Therapeutic potential of microRNAs for the treatment of renal fibrosis and CKD. Physiol Genomics 2017; 50:20-34. [PMID: 29127220 DOI: 10.1152/physiolgenomics.00039.2017] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Chronic kidney disease (CKD), defined as reduced glomerular filtration rate, is increasingly becoming a major public health issue. At the histological level, renal fibrosis is the final common pathway leading to end-stage renal disease, irrespective of the initial injury. According to this view, antifibrotic agents should slow or halt the progression of CKD. However, due to multiple overlapping pathways stimulating fibrosis, it has been difficult to develop antifibrotic drugs that delay or reverse the progression of CKD. MicroRNAs (miRNAs) are small noncoding RNA molecules, 18-22 nucleotides in length, that control many developmental and cellular processes as posttranscriptional regulators of gene expression. Emerging evidence suggests that miRNAs targeted against genes involved in renal fibrosis might be potential candidates for the development of antifibrotic therapies for CKD. This review will discuss some of the miRNAs, such as Let-7, miR-21,-29, -192, -200,-324, -132, -212, -30, -126, -433, -214, and -199a, that are implicated in renal fibrosis and the potential to exploit these molecular targets for the treatment of CKD.
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Affiliation(s)
- Wenshan Lv
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center , Jackson, Mississippi.,Department of Endocrinology and Metabolism, the Affiliated Hospital of Qingdao University , Qingdao , China
| | - Fan Fan
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center , Jackson, Mississippi
| | - Yangang Wang
- Department of Endocrinology and Metabolism, the Affiliated Hospital of Qingdao University , Qingdao , China
| | - Ezekiel Gonzalez-Fernandez
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center , Jackson, Mississippi
| | - Chen Wang
- Department of Endocrinology and Metabolism, the Affiliated Hospital of Qingdao University , Qingdao , China
| | - Lili Yang
- West Coast Clinic of Affiliated Hospital of Qingdao University , Qingdao , China
| | - George W Booz
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center , Jackson, Mississippi
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Leaf IA, Duffield JS. What can target kidney fibrosis? Nephrol Dial Transplant 2017; 32:i89-i97. [PMID: 28391346 DOI: 10.1093/ndt/gfw388] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 10/04/2016] [Indexed: 11/14/2022] Open
Abstract
Fibrosis, a characteristic of all chronic kidney diseases, is now recognized to be an independent predictor of disease progression. Deposition of pathological matrix in the walls of glomerular capillaries, the interstitial space and around arterioles both predicts and contributes to functional demise of the nephron and its surrounding vasculature. Recent identification of the major cell populations of fibroblast precursors in the kidney interstitium as pericytes and tissue-resident mesenchymal stem cells, and in the glomerulus as podocytes, parietal epithelial and mesangial cells, has enabled the study of the fibrogenic process in much greater depth directly in the fibroblast precursors. These cells are not only matrix-producing cells, but are also important innate immune surveillance cells that regulate the inflammatory process, exacerbate tissue damage by release of radicals and cytokines, and contribute to parenchymal and microvascular dysfunction by aberrant wound-healing responses. Innate immune signaling in fibroblasts and their precursors is intimately intertwined with the process of fibrogenesis. In addition, genomic and genetic studies also point to defective responses in loci close to genes involved in solute transport, metabolism, autophagy, protein handling and vascular homeostasis, principally in the epithelium and endothelium, as upstream drivers of the fibrotic process, indicating that cellular crosstalk is vital for development of fibrosis. As we move beyond TGFβ inhibition as a central target for fibrosis, targeting innate immune signaling and metabolic dysfunction appear increasingly tenable alternative targets for novel therapies.
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Affiliation(s)
- Irina A Leaf
- Research & Development, Biogen, Cambridge, MA, USA
| | - Jeremy S Duffield
- Research & Development, Biogen, Cambridge, MA, USA.,University of Washington, Seattle, WA, USA
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Jiang XP, Ai WB, Wan LY, Zhang YQ, Wu JF. The roles of microRNA families in hepatic fibrosis. Cell Biosci 2017; 7:34. [PMID: 28680559 PMCID: PMC5496266 DOI: 10.1186/s13578-017-0161-7] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Accepted: 06/26/2017] [Indexed: 12/17/2022] Open
Abstract
When hepatocytes are damaged severely, a variety of signaling pathways will be triggered by inflammatory factors and cytokines involving in the process of hepatic fibrosis. The microRNA (miRNA) family consists of several miRNAs which have the potential for synergistic regulation of these signaling pathways. However, it is poor to understand the roles of miRNA family as a whole in hepatic fibrosis. Increasing studies have suggested several miRNA families are related with activation of hepatic stellate cells and hepatic fibrosis through cooperatively regulating certain signaling pathways. During the process of hepatic fibrosis, miR-29 family primarily induces cell apoptosis by modulating phosphatidylinositol 3-kinase/AKT signaling pathway and regulates extracellular matrix accumulation. miR-34 family promotes the progression of hepatic fibrosis by inducing activation of hepatic stellate cells, while miR-378 family suppresses the process in Glis dependent manner. miR-15 family mainly promotes cell proliferation and induces apoptosis. The miR-199 family and miR-200 family are responsible for extracellular matrix deposition and the release of pro-fibrotic cytokines. These miRNA family members play pro-fibrotic or anti-fibrotic roles by targeting genes collectively or respectively which involve in hepatic fibrosis related signaling pathways and hepatic stellate cell activation. Thus, good understandings of molecular mechanisms which are based on miRNA families may provide new ideas for the molecular targeted therapy of hepatic fibrosis in the future.
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Affiliation(s)
- Xue-Ping Jiang
- Institute of Organ Fibrosis and Targeted Drug Delivery, China Three Gorges University, 8 Daxue Road, Xiling District, Yichang, 443002 China
| | - Wen-Bing Ai
- The Yiling Hospital of Yichang, 31 Donghu Road, Yi Ling District, Yichang, 443100 Hubei China
| | - Lin-Yan Wan
- Institute of Organ Fibrosis and Targeted Drug Delivery, China Three Gorges University, 8 Daxue Road, Xiling District, Yichang, 443002 China.,The RenMin Hospital, China Three Gorges University, 31 Huti Subdistrict, Xi Ling District, Yichang, 443000 Hubei China
| | - Yan-Qiong Zhang
- Institute of Organ Fibrosis and Targeted Drug Delivery, China Three Gorges University, 8 Daxue Road, Xiling District, Yichang, 443002 China
| | - Jiang-Feng Wu
- Institute of Organ Fibrosis and Targeted Drug Delivery, China Three Gorges University, 8 Daxue Road, Xiling District, Yichang, 443002 China
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Paul P, Chakraborty A, Sarkar D, Langthasa M, Rahman M, Bari M, Singha RS, Malakar AK, Chakraborty S. Interplay between miRNAs and human diseases. J Cell Physiol 2017; 233:2007-2018. [PMID: 28181241 DOI: 10.1002/jcp.25854] [Citation(s) in RCA: 280] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 02/07/2017] [Indexed: 12/12/2022]
Abstract
MicroRNAs (miRNAs) are endogenous, non-coding RNAs, which have evoked a great deal of interest due to their importance in many aspects of homeostasis and diseases. MicroRNAs are stable and are essential components of gene regulatory networks. They play a crucial role in healthy individuals and their dysregulations have also been implicated in a wide range of diseases, including diabetes, cardiovascular disease, kidney disease, and cancer. This review summarized the current understanding of interactions between miRNAs and different diseases and their role in disease diagnosis and therapy.
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Affiliation(s)
- Prosenjit Paul
- Department of Biotechnology, Assam University, Silchar, Assam, India
| | | | - Debasree Sarkar
- Department of Biotechnology, Assam University, Silchar, Assam, India
| | | | - Musfhia Rahman
- Department of Biotechnology, Assam University, Silchar, Assam, India
| | - Minakshi Bari
- Department of Biotechnology, Assam University, Silchar, Assam, India
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Xie J, Zhou Y, Gao W, Li Z, Xu Z, Zhou L. The relationship between amniotic fluid miRNAs and congenital obstructive nephropathy. Am J Transl Res 2017; 9:1754-1763. [PMID: 28469780 PMCID: PMC5411923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 09/26/2016] [Indexed: 06/07/2023]
Abstract
Exosomes are small membrane vesicles with size of 30-100 nm, which were found in bodily fluids including amniotic fluid and saliva. The biological materials in exosomes, such as proteins and RNA, can be used as novel potential biomarkers for diagnostic assays. The purpose of this study was to assess whether exosomal microRNAs (miRNAs) could be used as biomarkers to prenatally diagnose congenital hydronephrosis and to evaluate fetal kidney function. Transmission electron microscopy (TEM), flow cytometry (FACS), and western-blot were applied to identify exosomes in the amniotic fluid from fetuses with congenital hydronephrosis and healthy controls. Exosomal miRNA was extracted according to the manufacturer's protocol and used for microarray. The differentially expressed miRNAs were selected for further study. The miRNA targets were analyzed to assess their possible function in the pathophysiology of obstructive nephropathy, and the miRNA array results were confirmed by qPCR. Amniotic fluid exosomes were identified based on CD24 and CD9 expression. The has-miR-942, has-miR-4289, has-miRPlus-A1073, and has-miR-195-3p were up-regulated in amniotic fluid exosomes from fetuses with congenital hydronephrosis comparing with those in healthy controls, and 35 had reduced expression levels. These results were confirmed by using qPCR. After integrating the miRNAs targets predicted via three databases and subjecting those target genes to KEGG pathway analysis, we found that the target genes of hsa-miR-300 and hsa-miR-299-5p were determined to be part of the Wnt signaling pathway. In addition, DVL2, PP2R5A, SRFP2, and SIAH1 predicted as target genes of has-miR-300 and has-miR-299-5p are informative for further exploration of congenital hydronephrosis pathologies. The reduced expression of hsa-miR-300 and hsa-miR-299-5p in the amniotic fluid of congenital hydronephrosis could be a biomarker for kidney fibrosis associated with congenital obstructive nephropathy.
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Affiliation(s)
- Juntao Xie
- Department of Pediatric Surgery, The First Affiliated Hospital, Sun Yat-sen UniversityGuangdong, People’s Republic of China
| | - Yi Zhou
- Department of Fetal Medical Center, The First Affiliated Hospital, Sun Yat-sen UniversityGuangdong, People’s Republic of China
| | - Wenzong Gao
- Department of Pediatric Surgery, The First Affiliated Hospital, Sun Yat-sen UniversityGuangdong, People’s Republic of China
| | - Zuoqing Li
- Department of Pediatric Surgery, The First Affiliated Hospital, Sun Yat-sen UniversityGuangdong, People’s Republic of China
| | - Zhe Xu
- Department of Pediatric Surgery, The First Affiliated Hospital, Sun Yat-sen UniversityGuangdong, People’s Republic of China
| | - Li Zhou
- Department of Pediatric Surgery, The First Affiliated Hospital, Sun Yat-sen UniversityGuangdong, People’s Republic of China
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Shen Y, Zhou M, Yan J, Gong Z, Xiao Y, Zhang C, Du P, Chen Y. miR-200b inhibits TNF-α-induced IL-8 secretion and tight junction disruption of intestinal epithelial cells in vitro. Am J Physiol Gastrointest Liver Physiol 2017; 312:G123-G132. [PMID: 27979826 DOI: 10.1152/ajpgi.00316.2016] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Revised: 11/18/2016] [Accepted: 11/30/2016] [Indexed: 01/31/2023]
Abstract
UNLABELLED Inflammatory bowel diseases (IBDs) are chronic, inflammatory disorders of the gastrointestinal tract with unclear etiologies. Intestinal epithelial cells (IECs), containing crypt and villus enterocytes, occupy a critical position in the pathogenesis of IBDs and are a major producer of immunoregulatory cytokines and a key component of the intact epithelial barrier. Previously, we have reported that miR-200b is involved in the progression of IBDs and might maintain the integrity of the intestinal epithelial barrier via reducing the loss of enterocytes. In this study, we further investigated the impact of miR-200b on intestinal epithelial inflammation and tight junctions in two distinct differentiated states of Caco-2 cells after TNF-α treatment. We demonstrated that TNF-α-enhanced IL-8 expression was decreased by microRNA (miR)-200b in undifferentiated IECs. Simultaneously, miR-200b could alleviate TNF-α-induced tight junction (TJ) disruption in well-differentiated IECs by reducing the reduction in the transepithelial electrical resistance (TEER), inhibiting the increase in paracellular permeability, and preventing the morphological redistribution of the TJ proteins claudin 1 and ZO-1. The expression levels of the JNK/c-Jun/AP-1 and myosin light chain kinase (MLCK)/phosphorylated myosin light chain (p-MLC) pathways were attenuated in undifferentiated and differentiated enterocytes, respectively. Furthermore, a dual-luciferase reporter gene detection system provided direct evidence that c-Jun and MLCK were the specific targets of miR-200b. Collectively, our results highlighted that miR-200b played a positive role in IECs via suppressing intestinal epithelial IL-8 secretion and attenuating TJ damage in vitro, which suggested that miR-200b might be a promising strategy for IBD therapy. NEW & NOTEWORTHY This was the first time that the inhibitory role of miR-200b on intestinal epithelial inflammation and paracellular permeability has been reported. Moreover, we further divided the intestinal epithelial cells (IECs) into two differentiated conditions and investigated the distinct impacts of miR-200b. Finally, we put forward and proved that myosin light chain kinase (MLCK) was a novel target of miR-200b.
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Affiliation(s)
- Yujie Shen
- Department of Gastroenterology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Zhou
- Department of Gastroenterology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Junkai Yan
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China; and
| | - Zizhen Gong
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China; and
| | - Yongtao Xiao
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China; and
| | - Cong Zhang
- Department of Gastroenterology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Peng Du
- Department of Colorectal Surgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yingwei Chen
- Department of Gastroenterology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; .,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China; and
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Abstract
The significant parallels between cell plasticity during embryonic development and carcinoma progression have helped us understand the importance of the epithelial-mesenchymal transition (EMT) in human disease. Our expanding knowledge of EMT has led to a clarification of the EMT program as a set of multiple and dynamic transitional states between the epithelial and mesenchymal phenotypes, as opposed to a process involving a single binary decision. EMT and its intermediate states have recently been identified as crucial drivers of organ fibrosis and tumor progression, although there is some need for caution when interpreting its contribution to metastatic colonization. Here, we discuss the current state-of-the-art and latest findings regarding the concept of cellular plasticity and heterogeneity in EMT. We raise some of the questions pending and identify the challenges faced in this fast-moving field.
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The cellular and signalling alterations conducted by TGF-β contributing to renal fibrosis. Cytokine 2016; 88:115-125. [DOI: 10.1016/j.cyto.2016.08.019] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Revised: 08/18/2016] [Accepted: 08/22/2016] [Indexed: 01/08/2023]
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48
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Cathepsin L is crucial for the development of early experimental diabetic nephropathy. Kidney Int 2016; 90:1012-1022. [DOI: 10.1016/j.kint.2016.06.035] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Revised: 06/22/2016] [Accepted: 06/30/2016] [Indexed: 11/20/2022]
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Abstract
Transforming growth factor-β (TGF-β) is the primary factor that drives fibrosis in most, if not all, forms of chronic kidney disease (CKD). Inhibition of the TGF-β isoform, TGF-β1, or its downstream signalling pathways substantially limits renal fibrosis in a wide range of disease models whereas overexpression of TGF-β1 induces renal fibrosis. TGF-β1 can induce renal fibrosis via activation of both canonical (Smad-based) and non-canonical (non-Smad-based) signalling pathways, which result in activation of myofibroblasts, excessive production of extracellular matrix (ECM) and inhibition of ECM degradation. The role of Smad proteins in the regulation of fibrosis is complex, with competing profibrotic and antifibrotic actions (including in the regulation of mesenchymal transitioning), and with complex interplay between TGF-β/Smads and other signalling pathways. Studies over the past 5 years have identified additional mechanisms that regulate the action of TGF-β1/Smad signalling in fibrosis, including short and long noncoding RNA molecules and epigenetic modifications of DNA and histone proteins. Although direct targeting of TGF-β1 is unlikely to yield a viable antifibrotic therapy due to the involvement of TGF-β1 in other processes, greater understanding of the various pathways by which TGF-β1 controls fibrosis has identified alternative targets for the development of novel therapeutics to halt this most damaging process in CKD.
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Epigenetics in Kidney Transplantation: Current Evidence, Predictions, and Future Research Directions. Transplantation 2016; 100:23-38. [PMID: 26356174 DOI: 10.1097/tp.0000000000000878] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Epigenetic modifications are changes to the genome that occur without any alteration in DNA sequence. These changes include cytosine methylation of DNA at cytosine-phosphate diester-guanine dinucleotides, histone modifications, microRNA interactions, and chromatin remodeling complexes. Epigenetic modifications may exert their effect independently or complementary to genetic variants and have the potential to modify gene expression. These modifications are dynamic, potentially heritable, and can be induced by environmental stimuli or drugs. There is emerging evidence that epigenetics play an important role in health and disease. However, the impact of epigenetic modifications on the outcomes of kidney transplantation is currently poorly understood and deserves further exploration. Kidney transplantation is the best treatment option for end-stage renal disease, but allograft loss remains a significant challenge that leads to increased morbidity and return to dialysis. Epigenetic modifications may influence the activation, proliferation, and differentiation of the immune cells, and therefore may have a critical role in the host immune response to the allograft and its outcome. The epigenome of the donor may also impact kidney graft survival, especially those epigenetic modifications associated with early transplant stressors (e.g., cold ischemia time) and donor aging. In the present review, we discuss evidence supporting the role of epigenetic modifications in ischemia-reperfusion injury, host immune response to the graft, and graft response to injury as potential new tools for the diagnosis and prediction of graft function, and new therapeutic targets for improving outcomes of kidney transplantation.
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