Lack of microRNA-155 ameliorates renal fibrosis by targeting PDE3A/TGF-β1/Smad signaling in mice with obstructive nephropathy.

Abstract

Although microRNA-155 (miR-155) is implicated in the pathogenesis of several fibrotic diseases, information regarding its functional role in renal fibrosis is limited. The current study aims to investigate the effects of miR-155 on renal fibrosis in unilateral ureteral occlusion (UUO) mice. MiR-155 level was significantly increased in renal tissues of UUO mice and TGF-β1-treated HK2 cells. Masson's trichrome staining showed that delivery of adeno-associated virus encoding miR-155 inhibitor led to a decrease in renal fibrosis induced by UUO. The increased expression of plasminogen activator inhibitor type 1, collagen III and collagen IV was also inhibited after miR-155 inhibition. In addition, miR-155 knockdown also prevented TGF-β1-induced epithelial-mesenchymal transition, concomitantly with a restoration of E-cadherin expression and a decrease of vimentin expression. Computational analysis revealed that miR-155 directly targets at 3'UTR of PDE3A. Overexpression of miR-155 suppressed the luciferase activity and protein expression of PDE3A, whereas inhibition of miR-155 increased PDE3A luciferase activity and expression. Furthermore, miR-155 inhibited TGF-β1-induced the increase of TGF-β1 expression and Smad-2/3 phosphorylation in HK2 cells. In contrast, knockdown of PDE3A reversed the effect of miR-155 inhibition on TGF-β1 expression. This study demonstrates that knockdown of miR-155 attenuates renal fibrosis via inhibiting TGF-β1/Smad signaling activation by targeting the upstream molecule PDE3A. This study suggests that miR-155 inhibition may be a novel therapeutic approach for preventing fibrotic kidney diseases.