Knockdown of lncRNA PVT1 alleviates high glucose-induced proliferation and fibrosis in human mesangial cells by miR-23b-3p/WT1 axis

Abstract

Background: Diabetic nephropathy (DN) is a severe complication of diabetes with type 1 and 2. Long non-coding RNAs (lncRNAs) are being found to be involved in the DN pathogenesis. In this study, we aimed to further explore the effect and underlying mechanism of plasmacytoma variant translocation 1 (PVT1) in DN pathogenesis. Methods: The expression levels of PVT1, miR-23b-3p, and Wilms tumor protein 1 (WT1) mRNA were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). Western blot analysis was performed to determine protein expression. Cell proliferation was detected using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetr-azolium (MTS) assay. The targeted correlation between miR-23b-3p and PVT1 or WT1 was verified by dual-luciferase reporter assay. Results: PVT1 and WT1 were highly expressed in the serum of DN patients and high glucose (HG)-induced mesangial cells (MCs). The knockdown of PVT1 or WT1 ameliorated HG-induced proliferation and fibrosis in MCs. Mechanistically, PVT1 modulated WT1 expression through acting as a molecular sponge of miR-23b-3p. The miR-23b-3p/WT1 axis mediated the protective effect of PVT1 knockdown on HG-induced proliferation and fibrosis in MCs. The NF-κB pathway was involved in the regulatory network of the PVT1/miR-23b-3p/WT1 axis in HG-induced MCs. Conclusion: Our study suggested that PVT1 knockdown ameliorated HG-induced proliferation and fibrosis in MCs at least partially by regulating the miR-23b-3p/WT1/NF-κB pathway. Targeting PVT1 might be a potential therapeutic strategy for DN treatment.

Long Non-coding RNA: An Emerging Contributor and Potential Therapeutic Target in Renal Fibrosis

“…Furthermore, PVT1 knockdown blocks the PI3K/Akt/mTOR signal and promotes the apoptosis of MMCs under HG conditions by upregulating miR-93-5p (Li J. et al, 2020). Furthermore, Zhong et al (2020) validated that silencing PVT1 might relieve HGinduced FN and α-SMA expression and proliferation in hMCs by inhibiting the NF-κB pathway via the miR-23b-3p/WT1 axis.…”

“…PVT1, a 1.9-kb-long lncRNA, mediates the overexpression of ECM proteins in DN (Alvarez and DiStefano, 2011) and was the first lncRNA reported to be related to kidney disease (Alvarez et al, 2016). Accordingly, PVT1 is upregulated in the serum of patients with DN (Liu D. W. et al, 2019;Zhong et al, 2020). Similarly, PVT1 expression significantly increased in mouse podocyte clone-5 and in primary podocytes in an HG environment (Liu D. W. et al, 2019).…”

Long noncoding RNA MIAT inhibits the progression of diabetic nephropathy and the activation of NF-κB pathway in high glucose-treated renal tubular epithelial cells by the miR-182-5p/GPRC5A axis

“…The inhibitory effect of GPRC5A on NF-κB pathway has been discovered in lung inflammation [ 40 ]. PVT1 facilitated the HG-induced mesangial cell proliferation and fibrosis via sponging miR-23b-3p to result in the regulation of WT1 [ 41 ]. MALAT1 enhanced the DN progression in renal tubular epithelial cells by increasing NLRP3 level through playing the sponge role for miR-30c [ 42 ].…”

Non-Coding RNAs as Biomarkers and Therapeutic Targets for Diabetic Kidney Disease

“…Nevertheless, some lncRNAs interact with miRNAs to trigger and promote the fibrotic process. ( Yang et al, 2019a ; Jiang et al, 2020a ; Fu et al, 2020 ; Zhong et al, 2020 ). Interestingly, LINC00968 inhibits p21 by recruiting EZH2 to enhance proliferation and fibrosis of MCs ( Li et al, 2018b ).…”