The miR-200 family regulates TGF-β1-induced renal tubular epithelial to mesenchymal transition through Smad pathway by targeting ZEB1 and ZEB2 expression

Most chronic kidney injuries inevitably progress to irreversible renal fibrosis. Tubular epithelial-to-mesenchymal transition (EMT) is recognized to play pivotal roles in the process of renal fibrosis. However, a comprehensive understanding of the pathogenesis of renal scar formation and progression remains an urgent task for renal researchers. The endogenously produced microRNAs (miRNAs), proved to play important roles in gene regulation, probably regulate most genes involved in EMT. In this study, we applied microarray analysis to investigate the expression profiles of miRNA in murine interstitial fibrotic kidneys induced by unilateral ureteral obstruction (UUO). It was found that miR-200a and miR-141, two members of the miR-200 family, were downregulated at the early phase of UUO. In TGF-β1-induced tubular EMT in vitro, it was also found that the members of the miR-200 family were downregulated in a Smad signaling-dependent manner. It was demonstrated that the miR-200 family was responsible for protecting tubular epithelial cells from mesenchymal transition by target suppression of zinc finger E-box-binding homeobox (ZEB) 1 and ZEB2, which are E-cadherin transcriptional repressors. The results suggest that downregulation of the miR-200 family initiates the dedifferentiation of renal tubules and progression of renal fibrosis, which might provide important targets for novel therapeutic strategies.

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Augmenter of liver regeneration inhibits TGF-β1-induced renal tubular epithelial-to-mesenchymal transition via suppressing TβR II expression in vitro

Experimental Cell Research ◽

10.1016/j.yexcr.2014.07.001 ◽

2014 ◽

Vol 327 (2) ◽

pp. 287-296 ◽

Cited By ~ 5

Author(s):

Xiao-hui Liao ◽

Ling Zhang ◽

Guo-tao Chen ◽

Ru-yu Yan ◽

Hang Sun ◽

...

Keyword(s):

Liver Regeneration ◽

Epithelial To Mesenchymal Transition ◽

Mesenchymal Transition ◽

Augmenter Of Liver Regeneration ◽

Renal Tubular ◽

Tgf Β1

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Focal adhesion kinase mediates TGF-β1-induced renal tubular epithelial-to-mesenchymal transition in vitro

Molecular and Cellular Biochemistry ◽

10.1007/s11010-010-0396-7 ◽

2010 ◽

Vol 340 (1-2) ◽

pp. 21-29 ◽

Cited By ~ 39

Author(s):

Bingqing Deng ◽

Xiao Yang ◽

Jianshe Liu ◽

Fangfang He ◽

Zhonghua Zhu ◽

...

Keyword(s):

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Epithelial To Mesenchymal Transition ◽

Mesenchymal Transition ◽

Renal Tubular ◽

Tgf Β1

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Metformin Improves Epithelial-to-Mesenchymal Transition Induced by TGF-β1 in Renal Tubular Epithelial NRK-52E Cells via Inhibiting Egr-1

Journal of Diabetes Research ◽

10.1155/2018/1031367 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 9

Author(s):

Meiping Guan ◽

Wenqi Li ◽

Lingling Xu ◽

Yanmei Zeng ◽

Dan Wang ◽

...

Keyword(s):

Renal Fibrosis ◽

Epithelial To Mesenchymal Transition ◽

Transforming Growth Factor ◽

Mesenchymal Transition ◽

Early Growth Response ◽

Real Time Quantitative Pcr ◽

Novel Target ◽

Renal Tubular ◽

Tgf Β1 ◽

E Cadherin

The early growth response- (Egr-) 1 has been found to play a key role in organ fibrosis. Metformin has been shown to be effective in attenuating renal tubular epithelial-to-mesenchymal transition (EMT), which is involved in renal fibrosis. However, it is unknown whether metformin improves EMT via inhibiting Egr-1. In this study, rat renal tubular epithelial (NRK-52 E) cells, treated by transforming growth factor- (TGF-)β1 of 10 ng/ml with or without metformin of 1 mmol/l, were transfected by siEgr-1 or M61-Egr-1 plasmids to knock down or overexpress Egr-1, respectively. The gene and protein expressions of E-cadherin,α-SMA, fibronectin (FN), and Egr-1 were determined by real-time quantitative PCR and Western blotting, respectively. We observed that TGF-β1 significantly reduced E-cadherin expression and upregulated the expressions of FN,α-SMA, and Egr-1, which can be reversed by metformin. M61-Egr-1 transfection could exacerbate EMT, which can be reversed by metformin. Taken together, our data show that Egr-1 plays an important role in TGF-β1-induced EMT of renal tubular epithelial cells and metformin improves EMT while inhibiting Egr-1, which provides a potential novel target to combat renal fibrosis.

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Permissive effect of GSK3β on profibrogenic plasticity of renal tubular cells in progressive chronic kidney disease

Cell Death and Disease ◽

10.1038/s41419-021-03709-5 ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Bohan Chen ◽

Pei Wang ◽

Xianhui Liang ◽

Chunming Jiang ◽

Yan Ge ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Renal Fibrosis ◽

Binding Protein ◽

Renal Tubules ◽

Genetic Ablation ◽

Renal Tubular Cells ◽

Renal Tubular ◽

Renal Fibrogenesis ◽

Tgf Β1

AbstractRenal tubular epithelial cells (TECs) play a key role in renal fibrogenesis. After persistent injuries that are beyond self-healing capacity, TECs will dedifferentiate, undergo growth arrest, convert to profibrogenic phenotypes, and resort to maladaptive plasticity that ultimately results in renal fibrosis. Evidence suggests that glycogen synthase kinase (GSK) 3β is centrally implicated in kidney injury. However, its role in renal fibrogenesis is obscure. Analysis of publicly available kidney transcriptome database demonstrated that patients with progressive chronic kidney disease (CKD) exhibited GSK3β overexpression in renal tubulointerstitium, in which the predefined hallmark gene sets implicated in fibrogenesis were remarkably enriched. In vitro, TGF-β1 treatment augmented GSK3β expression in TECs, concomitant with dedifferentiation, cell cycle arrest at G2/M phase, excessive accumulation of extracellular matrix, and overproduction of profibrotic cytokines like PAI-1 and CTGF. All these profibrogenic phenotypes were largely abrogated by GSK3β inhibitors or by ectopic expression of a dominant-negative mutant of GSK3β but reinforced in cells expressing the constitutively active mutant of GSK3β. Mechanistically, GSK3β suppressed, whereas inhibiting GSK3β facilitated, the activity of cAMP response element-binding protein (CREB), which competes for CREB-binding protein, a transcriptional coactivator essential for TGF-β1/Smad signaling pathway to drive TECs profibrogenic plasticity. In vivo, in mice with folic acid-induced progressive CKD, targeting of GSK3β in renal tubules via genetic ablation or by microdose lithium mitigated the profibrogenic plasticity of TEC, concomitant with attenuated interstitial fibrosis and tubular atrophy. Collectively, GSK3β is likely a pragmatic therapeutic target for averting profibrogenic plasticity of TECs and improving renal fibrosis.

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Role of Stat3 Signaling in Control of EMT of Tubular Epithelial Cells During Renal Fibrosis

Cellular Physiology and Biochemistry ◽

10.1159/000480216 ◽

2017 ◽

Vol 42 (6) ◽

pp. 2552-2558 ◽

Cited By ~ 15

Author(s):

Jingsong Liu ◽

Ying Zhong ◽

Guoyong Liu ◽

Xiaobai Zhang ◽

Bofei Xiao ◽

...

Keyword(s):

Epithelial Cells ◽

Renal Injury ◽

Renal Fibrosis ◽

Critical Role ◽

Dependent Manner ◽

Tubular Epithelial Cells ◽

Mesenchymal Transition ◽

Stat3 Signaling ◽

Phosphorylated Stat3

Background/Aims: Transforming growth factor β 1 (TGFβ1) plays a critical role in the epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells (TECs) during renal injury, a major cause of acute renal failure, renal fibrosis and obstructive nephropathy. However, the underlying molecular mechanisms remain ill-defined. Here, we addressed this question. Methods: Expression of TGFβ1, Snail, and phosphorylated Stat3 was examined by immunohistochemistry in the kidney after induction of unilateral ureteral obstruction (UUO) in mice. In vitro, primary TECs were purified by flow cytometry, and then challenged with TGFβ1 with/without presence of specific inhibitors for phosphorylation of SMAD3 or Stat3. Protein levels were determined by Western blotting. Results: We detected significant increases in Snail and phosphorylated Stat3, an activated form for Stat3, in the kidney after induction of UUO in mice. In vitro, TGFβ1-challenged primary TECs upregulated Snail, in a SMAD3/Stat3 dependent manner. Conclusion: Our study sheds light on the mechanism underlying the EMT of TECs after renal injury, and suggests Stat3 signaling as a promising innovative therapeutic target for prevention of renal fibrosis.

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MKP2 inhibits TGF-β1-induced epithelial-to-mesenchymal transition in renal tubular epithelial cells through a JNK-dependent pathway

Clinical Science ◽

10.1042/cs20180602 ◽

2018 ◽

Vol 132 (21) ◽

pp. 2339-2355 ◽

Cited By ~ 6

Author(s):

Zhenzhen Li ◽

Xianghua Liu ◽

Fengyan Tian ◽

Ji Li ◽

Qingwei Wang ◽

...

Keyword(s):

Renal Fibrosis ◽

Epithelial To Mesenchymal Transition ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β1 ◽

Mitogen Activated Protein Kinase ◽

Jnk Signaling ◽

Mesenchymal Transition ◽

Amino Terminal ◽

Ureter Obstruction ◽

Tgf Β1

Epithelial-to-mesenchymal transition (EMT) is a phenotypic conversion that plays a crucial role in renal fibrosis leading to chronic renal failure. Mitogen-activated protein kinase phosphatase 2 (MKP2) is a member of the dual-specificity MKPs that regulate the MAP kinase pathway involved in transforming growth factor-β1 (TGF-β1)-induced EMT. However, the function of MKP2 in the regulation of EMT and the underlying mechanisms are still largely unknown. In the present study, we detected the expression of MKP2 in an animal model of renal fibrosis and evaluated the potential role of MKP2 in tubular EMT induced by TGF-β1. We found that the expression of MKP2 was up-regulated in the tubular epithelial of unilateral ureter obstruction rats. Meanwhile, we also demonstrated that TGF-β1 up-regulated MKP2 expression in NRK-52E cells during their EMT phenotype acquisition. Importantly, overexpression of MKP2 inhibited c-Jun amino terminal kinase (JNK) signaling and partially reversed EMT induced by TGF-β1. Moreover, reducing MKP2 expression enhanced JNK phosphorylation, promoted the E-cadherin suppression and induced α-SMA expression and fibronectin secretion in response to TGF-β1, which could be rescued by a JNK inhibitor. These results provide the first evidence that MKP2 is a negative feedback molecule induced by TGF-β1, and MKP2 overexpression inhibits TGF-β1-induced EMT through the JNK signaling pathway. MKP2 could be a promising target to be used in gene therapy for renal fibrosis.

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