Atorvastatin Regulates MALAT1/miR-200c/NRF2 Activity to Protect Against Podocyte Pyroptosis Induced by High Glucose

Abstract

Background Diabetic nephropathy (DN) is one of the main complications of diabetes mellitus (DM), which leads to the long-term loss of kidney functions. Long noncoding RNAs (LncRNAs) can alleviate DN by interacting with microRNAs (miRNAs). In this work, we aimed to explore the effects of the MALAT1/miR-200c/NRF2 regulatory axis on the pyroptosis and oxidative stress (Oxidative stress, OS) of renal podocytes in high glucose (HG) environment and whether the lipid-lowering drug atorvastatin (AT) can relieve renal OS through this approach. Methods MPC-5, a mouse podocyte cell line, was induced by HG as a cell model. The protein expressions of caspase-1, GSDMD, NLRP3, NRF2, etc. were detected by Western blotting and immunofluorescence, and the mRNA level of caspase-1, GSDMD, NLRP3, NRF2, MALAT1, miR-200c was tested by qRT-PCR. The cell pyroptosis of podocytes treated with AT was verified by CCK-8 or flow cytometry. The levels of Malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) were measured by spectrophotometer, respectively. Results The caspase-1 was upregulated in time-dependent manner and got the peak at 48 h and 30 mmol/L respectively in MPC-5 cells treated with HG. Further, the expression of GSDMD, MALAT1 and miR-200c were increased, while the level of NRF2, HO-1, OS-related indicators, were decreased simultaneously. Knockdown the MALAT1 protected MPC-5 cells from pyroptosis and OS induced by HG. However, overexpressing miR-200c in control-group cells increased pyroptosis and upregulated the OS level with HG culture medium. Further, atorvastatin protected MPC-5 cells from cell pyroptosis and downregulated the level of renal OS via attenuating the expression of MALAT1 and miR-200c. Conclusion Atorvastatin protects podocyte cells via MALAT1/miR-200c/NRF2 signal pathway from pyroptosis and OS induced by HG.

Allicin Inhibits Osteosarcoma Growth by Promoting Oxidative Stress and Autophagy via the Inactivation of the lncRNA MALAT1-miR-376a-Wnt/β-Catenin Signaling Pathway

“…lncRNA regulates the progression of cells in a variety of ways which includes oxidative stress and autophagy. In diabetic nephropathy, MALAT1 regulated oxidative stress to promote the injury of podocyte cell via the miR-200c/NRF2 axis [48]. Knockdown of MALAT1 activated cell autophagy and inhibited the progression of atherosclerosis…”

Regulation of Oxidative Stress by Long Non-Coding RNAs in Vascular Complications of Diabetes

“…Hence, MALAT1 may also generate oxidative stress in diabetic renal tissues by regulating KLF5/ NOX4 signaling. Additionally, it has been demonstrated that the expression levels of Nrf2 and HO-1 are both elevated in mouse podocyte MPC-5 cells with MALAT1-3 siRNA under high glucose conditions [22]. As mentioned above, Nrf2 is a redox-sensitive transcription factor, which regulates the expression of various antioxidant enzymes via ARE [23].…”

Emerging Role of LncRNA Regulation for NLRP3 Inflammasome in Diabetes Complications

“…miR-200c overexpression can promote OS in endothelial cells and interact with MALAT1 structurally ( Li et al, 2016 ; Carlomosti et al, 2017 ). In addition, Zuo Y et al demonstrated that AT suppresses caspase-1, GSDMD, and NLRP3 expressions by regulating MALAT1/miR-200c/NRF2 activation to prevent podocyte pyrolysis and OS induced by high glucose ( Zuo et al, 2021 ). It opens a new door to AT-induced therapy for diabetes complications.…”