Long noncoding RNA growth arrest-specific transcript 5 alleviates renal fibrosis in diabetic nephropathy by downregulating matrix metalloproteinase 9 through recruitment of enhancer of zeste homolog 2.

Abstract

Diabetic nephropathy (DN) is a frequently occurred microvascular complication associated with type I and type II diabetes mellitus. The participation of long noncoding RNAs (lncRNAs) in diabetes-related microvascular complications has been reported extensively. We attempted to unveil the possible regulatory mechanism of lncRNA growth arrest-specific transcript 5 (GAS5) and matrix metalloproteinase 9 (MMP9), an important inflammatory protein, in the progression of DN. A rat DN model was induced by streptozocin (STZ). The low expression of GAS5 and high expression of MMP9 in DN rats with DN was then determined by RT-qPCR and western blot analysis, and lentivirus-mediated GAS5 overexpression was shown to ameliorate STZ-induced renal interstitial fibrosis (RIF) and inflammatory reaction in the kidney of DN rats. Moreover, MMP9 was found to be upregulated in STZ-induced DN, while MMP9 silencing induced by lentivirus expressing shRNA against MMP9 reduced RIF and suppressed inflammation in the kidney of DN rats. RIP, RNA pull-down, and ChIP assays demonstrated that GAS5 downregulated MMP9 via recruiting enhancer of zeste homolog 2 (EZH2) in the promoter region of MMP9. Overall, our study reveals that GAS5 downregulates MMP9 expression through recruiting EZH2 to MMP9 promoter region and alleviates the progression of renal fibrosis in DN rats, which sheds new light on the therapeutic potential of GAS5-targeted therapies in combating that disease.