Carnosine alleviates cisplatin-induced acute kidney injury by targeting Caspase-1 regulated pyroptosis

Abstract

Acute kidney injury (AKI) is a syndrome characterized by rapid loss of renal excretory function. Its underlying mechanisms remain unclear. Pyroptosis, a form of programmed cell death, plays an important role in AKI. It is characterized by cell swelling and membrane rupture, triggering the release of cellular contents and activating robust inflammatory responses. Carnosine, a dipeptide with antioxidant and anti-inflammatory properties, has therapeutic effects in AKI. However, the mechanism by which carnosine treats AKI-associated pyroptosis remains unexplored. In this study, we investigated the protective effect of carnosine on renal tubule cells using in vivo and in vitro models of AKI. We found that carnosine therapy significantly alleviated altered serum biochemical markers and histopathological changes in mice with cisplatin-induced AKI. It also reduced the levels of inflammation and pyroptosis. These results were consistent with those seen in human kidney tubular epithelial cells (HK-2) treated with cisplatin. Through molecular docking and cellular thermal shift assay, we identified caspase-1 as a target of carnosine. By knocking down caspase-1 in HK-2 cells using caspase-1 siRNA, we demonstrated that carnosine did not exhibit a protective role in cisplatin-induced HK-2 cells. This study provides the first evidence that carnosine alleviates damage to kidney tubular epithelial cells by targeting caspase-1 and inhibiting pyroptosis. Therefore, carnosine holds promise as a potential therapeutic agent for AKI, with caspase-1 representing an effective therapeutic target in this pathology.

Keywords: Acute kidney injury; Carnosine; Caspase-1; Cisplatin; Pyroptosis.