Maintaining homeostasis of mitochondria and endoplasmic reticulum with NSC228155 alleviates cisplatin-induced acute kidney injury

Abstract

Acute kidney injury (AKI) is a common complication of hospitalization with high mortality. Approximately 30% of patients receiving cisplatin, the first-line chemotherapy treatment, develop AKI. NSC228155 is a novel compound with potential anti-cancer and anti-bacterial effects. Its therapeutic efficacy in other diseases is unclear. In the present study, we investigated the effect of NSC228155 on cisplatin-induced AKI. The mice were consecutively treated with 2.5 mg/kg of NSC228155 for five days and injected with cisplatin (22 mg/kg) via intraperitoneal injection on day three. NSC228155 strikingly improved the renal function by decreasing the serum creatinine by 52.6% in the cisplatin-induced AKI mice model. Pathologically, NSC228155 profoundly alleviated the tubular damage in Periodic Acid-Schiff staining, and significantly reduced the expression of tubular injury markers and apoptosis in the cisplatin-injured mice kidneys. NSC228155 effectively restored the mitochondrial homeostasis by decreasing damaged mitochondria, activating signals for mitochondrial dynamics and recycling, and corrected mitochondrial dysfunction in ATP production and oxidative stress in the cisplatin model. Transcriptomics and metabolomics analysis on the mice renal cortex suggested that NSC228155 profoundly corrected energy metabolism, especially citrate cycle-related pathways, oxidative stress, and endoplasmic reticulum (ER) stress in the cisplatin-induced AKI kidneys. NSC228155 effectively inhibited ER stress induced by cisplatin or tunicamycin in mice kidneys and HK-2 cells. Co-treatment of NSC228155 with 4-phenylbutyrate or MnTBAP showed a similar therapeutic effect in AKI as the inhibitors or NSC228155 alone did, and corrected the mitochondrial dysfunction and ER stress, respectively, indicating the crosstalk between ER and mitochondria played essential roles in the therapeutic effect of NSC228155 in AKI. Together, these results consistently demonstrated that NSC228155 alleviated cisplatin-induced AKI by restoring the homeostasis in mitochondria and ER, suggesting a therapeutic potential and perhaps a novel strategy for drug discovery.