Perilipin 2 Drives Age-Specific Responses to Cisplatin-Induced AKI

Background: Cisplatin is a widely used chemotherapeutic agent, but its dose-limiting nephrotoxicity, particularly in older patients, remains a major clinical concern. Disruption of lipid metabolism has emerged as a key contributor to Cisplatin-induced AKI. Perilipin 2 (Plin2), a lipid droplet (LD)-coating protein, regulates intracellular lipid metabolism and marks lipid accumulation in tubular cells during injury. However, the role of Plin2 in modulating cisplatin-induced AKI across different ages remains unclear. Methods: We employed a multidisciplinary approach involving young and aged Plin2 knockdown mice subjected to Cisplatin-induced AKI. Molecular pathology, proteomics, and bioinformatics were conducted, complemented by in vitro validation experiments. Results: Plin2 expression was induced in the kidneys after Cisplatin-induced AKI, with aged kidneys showing markedly higher levels compared to young counterparts. At baseline, aged mice also exhibited elevated Plin2 expression in the livers, which further increased after cisplatin treatment. In contrast, cardiac Plin2 expression declined with age and was further suppressed in young mice following injury. Functionally, Plin2 knockdown in aged mice did not impact renal outcomes after AKI. However, in both male and female young mice, Plin2 knockdown substantially improved renal function and reduced tubular cell death and inflammation after Cisplatin injection. Impressively, proteomic profiling revealed minimal changes in key regulators of fatty acid oxidation and glycolysis pathways after Plin2 knockdown. Instead, a marked increase in 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2), a rate-limiting enzyme in ketogenesis, was observed in Plin2 knockdown kidneys. Mechanistically, Plin2 may regulate energy metabolism by interacting with sirtuin 5 to desuccinylate and activate Hmgcs2, thereby enhancing ketone production and improving cellular energetics for repair during AKI. Conclusion: Plin2 governs Cisplatin-induced AKI in an age-dependent manner, likely through modulation of ketogenesis. Funding: NIDDK Support