Critical role of serum response factor in podocyte epithelial–mesenchymal transition of diabetic nephropathy

Zhao, Liang; Wang, Xueling; Sun, Lina; Nie, Huibin; Liu, Xiangchun; Chen, Zhuo; Guan, Guangju

doi:10.1177/1479164115588545

Cited by 17 publications

(10 citation statements)

References 31 publications

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“…The lifespan of Mkl1/Mkl2 dKO mice was over 10 weeks, slightly longer than Srf KO mice. Previous studies showed an injury-promoting role of SRF/MKL in kidney disease [25][26][27][28] ; in contrast, data here support SRF and MKL1/MKL2 in the maintenance of normal podocyte structure and function.…”

Section: Significance Statementcontrasting

confidence: 54%

Serum Response Factor Is Essential for Maintenance of Podocyte Structure and Function

Guo

Lyu

Slivano

et al. 2017

JASN

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Podocytes contain an intricate actin cytoskeleton that is essential for the specialized function of this cell type in renal filtration. Serum response factor (SRF) is a master transcription factor for the actin cytoskeleton, but the expression and function of SRF in podocytes are unknown. We found that SRF protein colocalizes with podocyte markers in human and mouse kidneys. Compared with littermate controls, mice in which the gene was conditionally inactivated with - exhibited early postnatal proteinuria, hypoalbuminemia, and azotemia. Histologic changes in the mutant mice included glomerular capillary dilation and mild glomerulosclerosis, with reduced expression of multiple canonical podocyte markers. We also noted tubular dilation, cell proliferation, and protein casts as well as reactive changes in mesangial cells and interstitial inflammation. Ultrastructure analysis disclosed foot process effacement with loss of slit diaphragms. To ascertain the importance of SRF cofactors in podocyte function, we disabled the myocardin-related transcription factor A and B genes. Although loss of either SRF cofactor alone had no observable effect in the kidney, deficiency of both recapitulated the -null phenotype. These results establish a vital role for SRF and two SRF cofactors in the maintenance of podocyte structure and function.

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Section: Significance Statementcontrasting

confidence: 54%

Serum Response Factor Is Essential for Maintenance of Podocyte Structure and Function

Guo

Lyu

Slivano

et al. 2017

JASN

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“… 31 α-SMA is a useful cytoskeletal biomarker of EMT, which has been detected in the fibrotic process of various organs undergoing EMT. 32 – 34 TGF-β is an inducer of EMT and initiates EMT by regulating transcriptional, posttranscriptional, translational, and posttranslational levels. 35 Increased TGF-β expression has been linked to EMT in renal fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Hyperglycemia activates the renin-angiotensin system and induces epithelial-mesenchymal transition in streptozotocin-induced diabetic kidneys

Chen

Juan

Chou

2018

J Renin Angiotensin Aldosterone Syst

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Introduction:The renin–angiotensin system and epithelial–mesenchymal transition play crucial roles in the development of kidney fibrosis. The connection between the renin–angiotensin system and transforming growth factor-β in epithelial–mesenchymal transition remains largely unknown.Materials and methods:We assessed oxidative stress, cytokine levels, renal morphology, profibrotic growth factor and renin–angiotensin system component expression, and cell-specific E- and N-cadherin expression in the kidneys of gerbils with streptozotocin-induced diabetes mellitus.Results:Animals in the experimental group received an intraperitoneal injection of streptozotocin to induce diabetes. The diabetic gerbil kidneys presented kidney injury, which was manifested as distorted glomeruli, necrosis of tubular cells, dilated tubular lumen, and brush border loss. Additionally, the diabetic gerbil kidneys exhibited significantly higher expressions of 8-hydroxy-2′-deoxyguanosine, nuclear factor-kB, toll-like receptor 4, tumor necrosis factor-α, transforming growth factor-β, connective tissue growth factor, α-smooth muscle actin, and N-cadherin and higher collagen deposition than did the control gerbil kidneys. Compared with the control kidneys, the diabetic gerbil kidneys exhibited significantly lower E-cadherin expression. These epithelial–mesenchymal transition characteristics were associated with an increase in renin–angiotensin system expression in the diabetic gerbils.Conclusions:We demonstrate that hyperglycemia activated the renin–angiotensin system, induced epithelial–mesenchymal transition, and contributed to kidney fibrosis in an experimental diabetes mellitus model.

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“…These methods were described previously. 15 All primer sequences are reported in Table 1. siRNA and luciferase assay SRF siRNA (5 0 -GACCTGCCTCAACTCGCCAGAC-3 0 ) was described previously. 16 786-O cells were transfected with the pcDNA 3.1 or pcDNA-SRF plasmid and non-specific siRNA or SRF siRNA along with empty vector or pGL3-Snail plasmid using HiPerFect Transfection Reagent (Qiagen, Hilden, Germany).…”

Section: Plasmids and Transfection Quantitative Rt-pcr Western Blotmentioning

confidence: 99%

Serum response factor increases renal cell carcinoma migration and invasion through promoting epithelial–mesenchymal transition

Zhao¹,

Li²,

Jiang³

et al. 2020

Int J of Urology

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Objective To explore the regulation and function of serum response factor in epithelial–mesenchymal transition in renal cell carcinoma. Methods First, bioinformatics analysis of human renal cell carcinoma tissues was carried out. Then, the expression of serum response factor, mesenchymal markers (N‐cadherin, vimentin and fibronectin) and epithelial markers (zonula occludens‐1 and epithelial cadherin) was examined in 786‐O cells (a human renal cell carcinoma cell line). Serum response factor was overexpressed with pcDNA‐serum response factor plasmid, and suppressed by CCG‐1423 (a small molecule inhibitor of serum response factor) to study how serum response factor affects epithelial–mesenchymal transition in renal cell carcinoma. A xenograft nude mouse model was established to explore whether serum response factor affected the tumorigenic ability of renal cell carcinoma cells. Results Serum response factor interacted with several important differentially expressed genes in renal cell carcinoma. In 786‐O cells, serum response factor, N‐cadherin, vimentin and fibronectin were upregulated, whereas zonula occludens‐1 and epithelial cadherin were downregulated. Serum response factor upregulation in 786‐O cells increased the Snail expression. Serum response factor suppression reduced Snail induction, and migration and invasion in renal cell carcinoma, which decreased the xenograft tumor volume. Conclusions Serum response factor is a critical transcription factor in human renal cell carcinoma. Increased serum response factor activity induces epithelial–mesenchymal transition, migration and invasion in 786‐O cells, and facilitates the progression of renal cell carcinoma. Targeting serum response factor with CCG‐1423 might be an attractive therapeutic strategy for renal cell carcinoma.

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Critical role of serum response factor in podocyte epithelial–mesenchymal transition of diabetic nephropathy

Abstract: Together, increased serum response factor activity provokes podocytes' epithelial-mesenchymal transition and dysfunction in diabetic nephropathy. Targeting serum response factor by small-molecule inhibitor may be an attractive therapeutic strategy for diabetic nephropathy.

Cited by 17 publications

References 31 publications

Serum Response Factor Is Essential for Maintenance of Podocyte Structure and Function

Serum Response Factor Is Essential for Maintenance of Podocyte Structure and Function

Hyperglycemia activates the renin-angiotensin system and induces epithelial-mesenchymal transition in streptozotocin-induced diabetic kidneys

Serum response factor increases renal cell carcinoma migration and invasion through promoting epithelial–mesenchymal transition

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