Silencing of long noncoding RNA PVT1 inhibits podocyte damage and apoptosis in diabetic nephropathy by upregulating FOXA1

Abstract

The number of patients with diabetic nephropathy (DN) is still on the rise worldwide, and this requires the development of new therapeutic strategies. Recent reports have highlighted genetic factors in the treatment of DN. Herein, we aimed to study the roles of long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) and histone 3 lysine 27 trimethylation (H3K27me3) in DN. A model of DN was established by inducing diabetes in mice with streptozotocin. Mouse podocyte clone 5 (MPC5) podocytes and primary podocytes were cultured in normal and high glucose media to observe cell morphology and to quantify PVT1 expression. The roles of PVT1 and enhancer of zeste homolog 2 (EZH2) were validated via loss-of-function and gain-of-function in vitro experiments to identify the interactions among PVT1, EZH2, and forkhead box A1 (FOXA1). The podocyte damage and apoptosis due to PVT1 and FOXA1 were verified with in vivo experiments. PVT1 was highly expressed in MPC5 and primary podocytes in DN patients and in cultures grown in high glucose medium. A large number of CpG (C-phosphate-G) island sites were predicted at the FOXA1 promoter region, where PVT1 recruited EZH2 to promote the recruitment of H3K27me3. The silencing of PVT1 or the overexpression of FOXA1 relieved the damage and inhibited the apoptosis of podocytes in DN, as was evidenced by the upregulated expression of synaptopodin and podocin, higher expression of Bcl-2, and lower expression of Bax and cleaved caspase-3. The key findings of this study collectively indicate that the suppression of lncRNA PVT1 exerts inhibitory effects on podocyte damage and apoptosis via FOXA1 in DN, which is of clinical significance.

Long noncoding RNA NEAT1 suppresses hepatocyte proliferation in fulminant hepatic failure through increased recruitment of EZH2 to the LATS2 promoter region and promotion of H3K27me3 methylation

“…Interestingly, our findings demonstrated that lncRNA NEAT1 modulated LATS2 expression through increased recruitment of EZH2 to the LATS2 promoter and promoted the methylation of H3K27 to H3K27me3. Likewise, it has also been indicated that lncRNA plasmacytoma variant translocation 1 can recruit EZH2 to elevate the accumulation of H3K27me3 41 , which further validates our results.…”

Noncoding RNAs in Diabetic Nephropathy: Pathogenesis, Biomarkers, and Therapy

“…Additionally, PVT1, a well-studied lncRNA, was highly expressed in primary podocytes in DN patients. The silencing of lncRNA PVT1 exerted inhibitory effects on podocyte damage and apoptosis via upregulating FOXA1 [80]. More importantly, lncRNA SOX2OT was confirmed to mitigate podocyte injury induced by the high glucose through autophagy induction by the miR-9/SIRT1 axis.…”

Research Progress on the Pathological Mechanisms of Podocytes in Diabetic Nephropathy

“…Upregulated β -arrestin 1/2 promoted podocyte apoptosis and the p53 pathway by increasing Bax, cleaved-caspase-3, and p-p53 levels in HG-induced podocytes [ 125 ]. High expression of PVT1 or low expression of FOXA1 can downregulate the expression of synaptophysin and podocyte protein, decrease the expression of Bcl-2, and increase the expression of Bax and cleaved-caspase-3, thus promoting podocyte apoptosis [ 126 ]. Chen et al [ 127 ] found that Sam68 was upregulated in a time- and dose-dependent manner in in vitro HG-treated podocytes.…”