SRP14 Triggers Apoptosis in Renal Tubules to Exacerbate AKI Through an Interaction with RPS7

To explore potential targets for acute kidney injury (AKI), we exposed renal tubular epithelial cells (RTECs) to a hypoxia/reoxygenation environment and conducted labeling-free proteomics. This treatment significantly increased signal recognition particle 14 (SRP14) in apoptotic RTECs. SRP14 was elevated in the serum of patients with AKI. The SRP14 expression was increased in the renal tubules of patients with acute tubular necrosis, as well as in four AKI mouse models following the procedures of ischemia-reperfusion injury (IRI), cecal ligation and puncture, and treatment with lipopolysaccharide and cisplatin. SRP14 appears to play a crucial role in the apoptosis of RTECs, as evidenced by an IRI-induced AKI model in tubule-specific Srp14 knockout mice. Furthermore, SRP14 triggered apoptosis in renal tubules upon renal IRI via the ribosomal protein S7 (RPS7)-mediated tumor protein p53 (TP53)–MDM2 proto-oncogene (MDM2) pathway. We screened an apoptosis-specific library containing 356 US Food and Drug Administration–approved compounds to identify those that inhibit RPS7. We identified nafamostat mesilate as a potent RPS7 inhibitor that attenuated renal IRI by inhibiting RTEC apoptosis. These findings suggest that SRP14 triggers apoptosis in RTECs to exacerbating AKI through an interaction with RPS7, which may be a therapeutic target for nafamostat mesylate to alleviate AKI.