Tanshinone IIA suppresses ferroptosis to attenuate renal podocyte injury in diabetic nephropathy through the embryonic lethal abnormal visual‐like protein 1 and acyl‐coenzyme A synthetase long‐chain family member 4 signaling pathway

Abstract

AbstractAims/IntroductionTanshinone IIA (TIIA) is one of the main components of the root of the red‐rooted Salvia miltiorrhiza Bunge. However, the molecular mechanisms underlying TIIA‐mediated protective effects in diabetic nephropathy (DN) are still unclear.Materials and MethodsHigh glucose (HG)‐induced mouse podocyte cell line (MPC5) cells were used as the in vitro model of DN and treated with TIIA. Cell viability, proliferation and apoptosis were detected using 3‐(4, 5‐dimethylthiazolyl‐2)‐2, 5‐diphenyltetrazolium bromide, 5‐ethynyl‐2′‐deoxyuridine and flow cytometry assays. The protein levels were assessed using western blot assay. The levels of inflammatory factors were deleted by enzyme‐linked immunoassay. Fe+ level, reactive oxygen species, malondialdehyde and glutathione products were detected using special assay kits. After ENCORI prediction, the interaction between embryonic lethal abnormal visual‐like protein 1 (ELAVL1) and acyl‐coenzyme A synthetase long‐chain family member 4 (ACSL4) was verified using co‐immunoprecipitation assay and dual‐luciferase reporter assays. ACSL4 messenger ribonucleic acid expression was measured using real‐time quantitative polymerase chain reaction.ResultsTIIA repressed HG‐induced MPC5 cell apoptosis, inflammatory response and ferroptosis. ACSL4 upregulation relieved the repression of TIIA on HG‐mediated MPC5 cell injury and ferroptosis. ELAVL1 is bound with ACSL4 to positively regulate the stability of ACSL4 messenger ribonucleic acid. TIIA hindered HG‐triggered MPC5 cell injury and ferroptosis by regulating the ELAVL1–ACSL4 pathway. TIIA blocked DN progression in in vivo research.ConclusionTIIA treatment restrained HG‐caused MPC5 cell injury and ferroptosis partly through targeting the ELAVL1–ACSL4 axis, providing a promising therapeutic target for DN treatment.