Abstract
Members of the miR-200 family of micro RNAs (miRNAs) have been shown to inhibit epithelial-mesenchymal transition (EMT). EMT of tubular epithelial cells is the mechanism by which renal fibroblasts are generated. Here we show that miR-200 family members inhibit transforming growth factor-beta (TGF-beta)-induced EMT of tubular cells. Unilateral ureter obstruction (UUO) is a common model of EMT of tubular cells and subsequent tubulointerstitial fibrosis. In order to examine the role of miR-200 family members in tubulointerstitial fibrosis, their expression was investigated in the kidneys of UUO mice. The expression of miR-200 family miRNAs was increased in a time-dependent manner, with induction of miR-200b most pronounced. To clarify the effect of miR-200b on tubulointerstitial fibrosis, we injected miR-200b precursor intravenously. A single injection of 0.5 nM miR-200b precursor was sufficient to inhibit the increase of collagen types I, III and fibronectin in obstructed kidneys, and amelioration of fibrosis was confirmed by observation of the kidneys with Azan staining. miR-200 family members have been previously shown to inhibit EMT by reducing the expression of ZEB-1 and ZEB-2 which are known repressors of E-cadherin. We demonstrated that expression of ZEB-1 and ZEB-2 was increased after ureter obstruction and that administration of the miR-200b precursor reversed this effect. In summary, these results indicate that miR-200 family is up-regulated after ureter obstruction, miR-200b being strongly induced, and that miR-200b ameliorates tubulointerstitial fibrosis in obstructed kidneys. We suggest that members of the miR-200 family, and miR-200b specifically, might constitute novel therapeutic targets in kidney disease.
Highlights
Micro RNAs are small non-coding RNA molecules that can regulate gene expression by interacting with multiple mRNAs and inducing either translational suppression or degradation of mRNA
A common model of renal tubulointerstitial fibrosis is the mouse model of unilateral ureter obstruction (UUO) [9]. Given their ability to inhibit epithelial-mesenchymal transition (EMT), we investigated whether injection of miR-200 micro RNAs (miRNAs) family precursors - chemically modified double strand of RNA which form RNA-induced silencing complex (RISC) like complex and can be processed by endonuclease Dicer into mature miR-200 family in cells - could ameliorate tubulointerstitial fibrosis by inhibition of EMT of tubular epithelial cells in UUO model mice
We investigated the role of miR-200 family members in EMT of tubular cells in UUO mice
Summary
Micro RNAs are small non-coding RNA molecules that can regulate gene expression by interacting with multiple mRNAs and inducing either translational suppression or degradation of mRNA. Recent reports have indicated that a double-negative feedback loop between ZEB1, ZEB2 and miRNA-200 family members regulates EMT in kidney tubular cells [4]. A common model of renal tubulointerstitial fibrosis is the mouse model of unilateral ureter obstruction (UUO) [9]. Given their ability to inhibit EMT, we investigated whether injection of miR-200 miRNA family precursors - chemically modified double strand of RNA which form RNA-induced silencing complex (RISC) like complex and can be processed by endonuclease Dicer into mature miR-200 family in cells - could ameliorate tubulointerstitial fibrosis by inhibition of EMT of tubular epithelial cells in UUO model mice
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