B-259 RNase L Deficiency Enhances Renal Self-Repair Following Nephrotoxin-induced Acute Kidney Injury via EGFR/AKT Activation and Apoptosis Inhibition

Background Acute kidney injury (AKI) is a commonly encountered clinical disorder with acute renal dysfunction, which is associated with high morbidity, mortality and a significant healthcare burden. The prevalence of AKI in hospitalized patients increased from 15.5% in 2011 to 26.8% in 2021 in the USA. Despite no effective therapy, AKI by itself can undergo a self-repair process, the degree of which may substantially affect its long-term endpoints. Exogenous administration of epidermal growth factor (EGF) has been found to promote renal repair by stimulating tubular cell regeneration in nephrotoxin-induced AKI. However, activation of the EGF receptor (EGFR) also contributes to development and progression of chronic kidney diseases (CKD). Clearly, the activation of EGF/EGFR plays an uncertain role, as it can be either beneficial or detrimental to renal function after AKI. A better understanding of its regulation in the kidney is, therefore, of importance. RNase L is a well-established regulator of cell proliferation and apoptosis, yet its function in kidney physiology remains largely unexplored. In this study, we investigated the role of RNase L in kidney function and renal recovery following AKI. Methods In the experiments, urine samples from mice were analyzed by LC-MS/MS to identify differential proteins. AKI mice model, induced in RNase L wild type (WT) and knockout (KO) mice by i.v. administration of folic acid (FA), was used to evaluate the role of RNase L in kidney damage and recovery following AKI. Urine, blood, and kidney tissues were collected. Kidney histology were evaluated by tissue staining, renal function parameters and complete blood count (CBC) were tested using veterinary chemistry analyzers. Molecular mechanisms involved were investigated by Western Blot analysis using both mice kidneys and HEK293 cells models. Results Deficiency of RNase L exclusively blocked the secretion of EGF in the urine of mice. In the AKI model, RNase L KO mice showed reduced kidney damage, less severe renal function impairment, and decreased systemic inflammation compared to WT mice. Furthermore, RNase L KO mice recovered much faster than RNase L WT mice from FA-induced AKI. Molecular analysis revealed that the EGFR-PI3K/AKT pathway was significantly activated, and apoptosis was inhibited, in the kidney of RNase L KO mice after FA treatment. This observation was further confirmed in RNase L KO kidney cells with and without EGF treatment. Conclusion Our study provides novel insights into the molecular mechanism underlying the regulation of the EGF/EGFR activation, which is vital in renal development, aging, physiology, and pathophysiology. Our findings suggest that RNase L may serve as a novel biomarker for predicting renal recovery following nephrotoxin-induced AKI, providing a potential tool for risk stratification and therapeutic decision-making.