Adiponectin protects against cisplatin-induced acute kidney injury via inhibiting caspase-1/GSDMD- and caspase-3/GSDME- mediated pyroptosis

Abstract

Acute kidney injury (AKI) is characterized by a sudden impairment of kidney function accounting for 10-15% of hospitalized patients in 2019. Nephrotoxic drug (e.g. Cisplatin) is one of risk factors for AKI. Pyroptosis is a programmed cell-death manifesting the disruption of the cell membrane, cell swelling and inflammation. Adiponectin (ADPN) is a multi-functional protein and is mainly released from adipose tissue. Previous studies indicated the level of ADPN was negatively associated with injuries of kidney diseases. However, the role of ADPN in kidney diseases remains largely unknown. Hereby, we hypothesized that ADPN might protect against cisplatin-induced nephrotoxicity via pyroptosis relevant pathways. In the present study, we aimed to (1) explore the role of ADPN on cisplatin-induced nephrotoxicity in vivo; (2) determine the mechanism in the ADPN mediated pathogenesis in cisplatin-induced nephrotoxicity in vivo; (3) determine the protective effect of ADPN in cisplatin-induced cytotoxicity in vitro.

In vivo study revealed that the deletion of ADPN in cisplatin-treated mice had a significant decline of renal functions and led to severe kidney injuries as demonstrated by analysis of serum creatinine and blood urea nitrogen examinations, and histological studies respectively. Genetic deficiency of ADPN in cisplatin-treated mice aggravated kidney injury which was negatively associated with activations of caspases-1/GSDMD-mediated and caspase-3/GSDME-mediated pyroptosis pathways. In vitro study indicated ADPN protected against the renal inflammation and cell death in cisplatin-induced cytotoxicity via suppressing both caspase-1/GSDMD-mediated and caspase-3/GSDME-mediated pyroptosis in kidney tubular epithelial cells.

In conclusion, ADPN protects against cisplatin-induced AKI via inhibiting caspase-1/GSDMD and caspase-3/GSDME mediated pyroptosis. The finding indicates ADPN could have therapeutic values for attenuating cisplatin-induced kidney injury.