PRMT1 facilitates the renal ischemia-reperfusion injury by inducing the ferroptosis via mediating the arginine methylation of ACSL4

Renal ischemia-reperfusion injury (IRI) potentially results in chronic kidney disease. Protein arginine methyltransferase 1 (PRMT1) is an arginine methyltransferase involved in regulating various cellular processes by methylating arginine residues. Herein, the function of PRMT1 in renal IRI was studied, and the underlying molecular mechanism was explored. HK-2 cells were stimulated by hypoxia/reoxygenation (H/R) to induce injury, and ferroptosis-related indicators were detected using commercialized kits and western blot. Renal ischemia-reperfusion (I/R) mouse model was established using PRMT1 knockout (PRMT1-KO) mice, and renal injury and ferroptosis were evaluated. The effect of PRMT1 on arginine methylation of acyl-CoA synthetase long-chain family member 4 (ACSL4) was evaluated using immunoprecipitation and western blot. The results showed that asymmetric dimethylarginine (ADMA) and PRMT1 levels were significantly increased in H/R-treated HK-2 cells. H/R reduced cell viability and induced ferroptosis in HK-2 cells, which was demonstrated by the use of deferoxamine (DFO), a ferroptosis inhibitor. Overexpression of PRMT1 facilitated ferroptosis, and knockdown of PRMT1 inhibited ferroptosis in H/R-induced cells. Moreover, knockout of PRMT1 attenuated I/R-induced renal injury and inhibited ferroptosis in the kidney tissues in mice, while overexpression of ASCL4 reversed these effects. Mechanistically, ASCL4 methylation level was upregulated by PRMT1 overexpressing, and R284 and R437 sites were the methylation sites in ACSL4. Furthermore, PRMT1 enhanced the stability of ACSL4 protein. In conclusion, PRMT1 facilitated the renal IRI by inducing the ferroptosis through promoting the arginine methylation of ACSL4. These findings indicate the therapeutic potential of PRMT1 for treating renal IRI.