miR-200b precursor can ameliorate renal tubulointerstitial fibrosis
Shigeyoshi Oba1, Shintaro Kumano, Etsu Suzuki
1Department of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo, Japan. OBA-2IM@h.u-tokyo.ac.jp
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.
Insights
MicroRNAs (miRNAs) of the miR-200 family inhibit kidney fibrosis by blocking epithelial-mesenchymal transition (EMT). miR-200b specifically reduces fibrosis markers and ZEB proteins in obstructed kidneys, suggesting therapeutic potential.
Area of Science:
- Nephrology
- Molecular Biology
- Biochemistry
Background:
- Epithelial-mesenchymal transition (EMT) in tubular cells generates renal fibroblasts, driving tubulointerstitial fibrosis.
- The miR-200 family of microRNAs (miRNAs) is known to inhibit EMT.
- Transforming growth factor-beta (TGF-beta) induces EMT in tubular cells.
Purpose of the Study:
- To investigate the role of miR-200 family members in unilateral ureter obstruction (UUO)-induced tubulointerstitial fibrosis.
- To determine the therapeutic potential of miR-200b in ameliorating kidney fibrosis.
Main Methods:
- Investigated miR-200 family expression in kidneys of UUO mice.
- Administered miR-200b precursor intravenously to UUO mice.
- Assessed collagen types I, III, fibronectin, ZEB-1, and ZEB-2 expression.
- Utilized Azan staining to evaluate fibrosis.
Main Results:
- miR-200 family miRNA expression, particularly miR-200b, increased time-dependently in UUO kidneys.
- Intravenous injection of miR-200b precursor inhibited collagen and fibronectin accumulation and ameliorated fibrosis.
- miR-200b administration reversed the UUO-induced increase in ZEB-1 and ZEB-2 expression.
Conclusions:
- miR-200 family members, especially miR-200b, are upregulated in response to ureter obstruction.
- miR-200b effectively ameliorates tubulointerstitial fibrosis in obstructed kidneys.
- miR-200 family members, particularly miR-200b, represent promising therapeutic targets for kidney disease.
