LncRNA MALAT1 facilities high glucose induced endothelial to mesenchymal transition and fibrosis via targeting miR-145/ZEB2 axis.

Abstract

Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus (DM), but the pathophysiology of DN is complex and not fully understood. Renal tubal epithelial-mesenchymal transition (EMT) has been shown to be the critical mechanism of glomerulosclerosis and tubulointerstitial fibrosis. However, the precise mechanisms underlying EMT are not clear. MALAT1 was found induced by hyperglycemia in kidney but whether MALAT1 is involved in renal tubal EMT remains unknown. The objective of our study is to explore the role of MALAT1 in hyperglycemia-induced EMT and fibrosis. We used db/db mouse and high glucose (HG)-stimulated HK-2 cells as in vivo and in vitro model of DN, respectively. qRT-PCR was used to measure levels of MALAT1 and miR-145. In addition, we validated interactions of MALAT1-miR-145 and miR-145-ZEB2 by dual luciferase reporter assays. Western blot was used to examine expressions of proteins involved in EMT and fibrosis. MALAT1 was upregulated while miR-145 was downregulated in renal tissues of db/db mice. Consistently, hyperglycemia significantly increased the level of MALAT1 but decreased miR-145 expression in a time-dependent manner in HK-2 cells. Furthermore, miR-145 binds to both MALAT1 and ZEB2. Knockdown MALAT1 or ZEB2 inhibited HG-induced EMT and fibrosis, similar to miR-145 overexpression. Our study is the first to show that MALAT1 and miR-145 regulate HG-induced EMT and fibrosis. Mechanistically, MALAT1 functions as a sponge RNA for miR-145 to derepress the expression of target gene ZEB2, thereby inducing EMT and fibrosis. These results provide a novel potential target for DN therapy in the future.