Cordycepin ameliorates ischemia/reperfusion-induced acute kidney injury via inhibiting apoptosis and necroptosis

Objective(s): Cordycepin (COR) is a natural bioactive compound derived from Cordyceps militaris. Relevant studies have shown that COR can alleviate kidney damage, but the underlying mechanism of its action in the treatment of acute kidney injury (AKI) remains to be further clarified.Materials and Methods: The GSE۱۴۸۴۲۰ dataset and GeneCards were used to identify AKI-related targets. GeneCards was used to obtain ischemia/reperfusion (I/R)-related targets. BATMAN ۱.۰ and GeneCards were used to identify potential drug targets of COR. Renal function, tissue damage, and molecular markers were assessed to explore the effects of COR on apoptosis and necroptosis in the treatment of AKI.Results: Network pharmacological analysis showed that AKI and COR shared ۲۸ drug targets. Enrichment analysis showed that the targets were involved in signaling pathways, including apoptosis and necroptosis. In vitro experiments revealed that COR alleviated hypoxia/re-oxygenation(H/R)-induced HK-۲ cells injury by reducing the expression of Bax and cleaved-Caspase۳ while increasing the expression of Bcl-۲. Necroptosis was lessened under COR treatment in vitro and in H/R-induced HK-۲ cells by reducing the expression of RIPK۱, RIPK۳, MLKL, and p-MLKL. COR and Nec-۱ (a RIPK۱ inhibitor) had the same inhibitory effect, confirming the role of COR in alleviating AKI by inhibiting RIPK۱-driven necroptosis. COR alleviated AKI by ameliorating renal morphology injury and pathological injury in vivo, manifested as a decrease in Scr and BUN levels, a significant reduction in the mRNA expression levels of KIM-۱ and NGAL, and a decrease in p-MLKL at the immunohistochemical level.Conclusion: COR may ameliorate I/R-induced AKI by inhibiting apoptosis and RIPK۱/RIPK۳/p-MLKL-mediated necroptosis.

کلیدواژه ها:

Acute kidney injury ، Apoptosis ، Cordycepin ، Necroptosis ، Receptor-Interacting ، Protein Serine-Threonine Kinase ۱ (RIPK۱)