Abstract
Diabetic nephropathy (DN) is one of the leading causes of end-stage renal diseases worldwide. This study is designed to investigate the underlying function and mechanism of a novel lncRNA GAS5 in the progression of DN. We found that lncRNA GAS5 expression level was decreased in type 2 diabetes (T2D) with DN compared with that in patients without DN. Moreover, lncRNA GAS5 expression level was negatively associated with the severity of DN-related complications. lncRNA GAS5 inhibited MCs proliferation and caused G0/1 phase arrest. lncRNA GAS5 overexpression alleviated the expression of fibrosis-related protein in mesangial cells (MCs). The dual-luciferase reporter assay and RNA binding protein immunoprecipitation (RIP) assay results revealed that lncRNA GAS5 functions as an endogenous sponge for miR-221 via both the directly targeting way and Ago2-dependent manner. Furthermore, SIRT1 was confirmed as a target gene of miR-221. lncRNA GAS5 upregulated SIRT1 expression and inhibited MCs proliferation and fibrosis by acting as an miR-221 sponge. Finally, we found that lncRNA GSA5 suppressed the development of DN in vivo. Thus, lncRNA GAS5 was involved in the progression of DN by sponging miR-221 and contributed to lncRNA-directed diagnostics and therapeutics in DN.
Highlights
Diabetic nephropathy (DN) poses considerable threat to public health [1, 2]
LncRNA GAS5 was downregulated in DN and negatively associated with the severity of DN-related complications
The aim of this study is to investigate the expression pattern and biological function of Long non-coding RNA (lncRNA) GAS5 in DN
Summary
Diabetic nephropathy (DN) poses considerable threat to public health [1, 2]. DN is one of the main complications of diabetes mellitus and the primary cause of renal failure [3]. A large number of studies have revealed that lncRNAs play a vital role in the development of DN. LncRNA MIAT upregulates the TGFβ1 signaling pathway and enhances diabetic retinopathy [7]. The downregulation of lncRNA H19 suppresses the abnormal differentiation of small intestinal epithelial cells by competing with miR-141-3p [8]. Growth arrest-specific 5 (GAS5, ID: 60674) is a novel marker in diabetes mellitus. LncRNA GAS5 inhibits invasion, epithelial-mesenchymal transition (EMT), proliferation, and invasion in oral squamous cell carcinoma by modulating the miR-21/PTEN pathway [11]. The knockdown of lncRNA GAS5 enhances the development of ovarian cancer by sponging miR-196-5p and modulating HOXA5 expression [12]. The biological function and potential mechanism of lncRNA GAS5 in DN are not fully understood
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