Carnosol alleviates cisplatin-induced acute kidney injury by regulating apoptosis and pyroptosis

The use of the common anticancer drug cisplatin (CP) in clinical practice often leads to acute kidney injury (AKI); however, no protective therapy is available. Therefore, new drugs that reduce the nephrotoxicity induced by CP are urgently needed. Carnosol (CA) is an antioxidant found. We investigated the renoprotective effects of CA on CP-induced AKI in male C57BL/6 mice and HK2 cells. CA mitigated renal dysfunction, histopathological changes and tubular injury in vivo, as indicated by the expression of NGAL, KIM1 and HMGB1. Moreover, the numbers of apoptotic cells and the expression of apoptotic proteins were dramatically reduced after CA treatment in mouse kidneys and HK2 cells. CA significantly ameliorated CP-induced inflammation and decreased TNF-alpha and IL-1 beta levels in vivo and in vitro and macrophage infiltration in the mouse kidney. CA decreased the expression levels of p-p65/p65, NLRP3 and ASC, which indicates that CA suppressed the activation of the NF-kappa B/NLRP3 signaling axis induced by CP in vivo and in vitro. In addition, CA decreased the levels of certain protein in pyroptotic cells, as indicated by the expression of cleaved caspase-1, GSDMD, and mature IL-1 beta and IL-18 in vivo and in vitro. Finally, CA reduced the level of cleaved caspase-1, but those of GSDMD and NLRP3 protein were not significantly different after treatment with the NLRP3 inhibitor MCC950 and were elevated by the NLRP3 activator nigericin. In conclusion, this study revealed that CA protects against CP-induced AKI by decreasing apoptosis and NF-kappa B/NLRP3/GSDMD-mediated pyroptosis, which provides new insight into the prevention of AKI.