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

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.

Carnosine attenuates renal ischemia-reperfusion injury by inhibiting GPX4-mediated ferroptosis.

Increasing evidence and our preliminary work have revealed the significant role of ferroptosis in acute kidney injury (AKI) induced by ischemia/reperfusion (IR). Carnosine (Car), a dipeptide consisting of ß-alanine and L-histidine, has been shown to ameliorate HG-induced tubular epithelial cells inflammation. Whether Car exerts protective effects on AKI, and its molecular mechanism have not been clarified. Our in vivo and in vitro IR-AKI mouse models demonstrated that Car alleviates kidney injury, inflammation and ferroptosis. In hypoxia/reoxygenation (HR) induced human renal tubular epithelial cells (HK2), Car treatment reduced lipid peroxidation and iron accumulation, suppressed oxidative stress, and inhibited ferroptosis. Through cellular thermal shift assay (CETSA) and molecular docking, we identified GPX4 as a potential target that binds with Car. Further study showed that overexpressed GPX4 had a comparable protective effect on HK2 cells under HR conditions, similar to Car. Additionally, our findings demonstrated that Car exhibited similar anti-ferroptosis effects in both folic acid (FA)-induced AKI mouse models and Erastin induced HK2 cells. In conclusion, our results highlight that Car alleviate renal IR injury by inhibiting GPX4-mediated ferroptosis. Car shows promise as a potential therapeutic drug for IR-AKI and other diseases associated with ferroptosis.