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

Abstract

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.

MicroRNA-494 Reduces ATF3 Expression and Promotes AKI

“…The relationship between CKD or other pathologically induced kidney diseases and miRNAs, like miR-200a, miR-200b, miR-141, miR-429, miR-205, miR-335, miR-34a and miR-192, has also been studied. [28][29][30][31] These studies have not mentioned miR-494, suggesting that the majority of miR-494 expression appears in the early phase of I/R injury and not in CKD or the other pathologically induced kidney diseases.…”

Inhibition of TBK1 attenuates radiation-induced epithelial–mesenchymal transition of A549 human lung cancer cells via activation of GSK-3β and repression of ZEB1

“…It is well documented that ZEB1 is an important transcript factor of EMT by inhibiting an E-box gene, such as E-cadherin. 36 Several previous studies suggest that ectopic expression of miR-200c hinders progression of EMT in TGF-b-treated cells by downregulation of ZEB1 37 and miR-200c induced endothelial cell apoptosis and senescence via ZEB1 inhibition. 38 ZEB1 is induced by TGFb during smooth muscle differentiation, in which it interacts with Smad3 and SRF to transactivate the genes encoding smooth muscle a-actin and smooth muscle myosin heavy chain.…”

MiR-19a promotes epithelial-mesenchymal transition through PI3K/AKT pathway in gastric cancer

“…Dysregulation of miRNAs is implicated in EMT modulation [25]. Gregory reported that miRNAs, such as smiR-200 family and miR-205, act as key modulators of EMT and enforcers of the epithelial phenotype targeting ZEB1 and SIP1 [26]. Dong et al demonstrated miR-194 directly targets BMI-1, and reverses EMT phenotype in endometrial cancer cells [27].…”