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Astragalin Inhibits Oxidative Stress‐Induced Pyroptosis and Apoptosis in Mouse Models of Renal Ischemia/Reperfusion Injury by Activating the SIRT1/Nrf2 Pathway

Qian Huang,Zilu Shi,Dandan Zheng,Huiqin Chen,Qiuhong Huang

Published 2025 in Phytotherapy Research

ABSTRACT

Natural flavonoid astragalin (AST) has many pharmacological effects and has been reported to improve renal injury in diabetic kidney disease. This study aimed to investigate the role of AST in renal ischemia/reperfusion injury (RIRI) and elucidate related mechanisms. The RIRI mouse models were pre‐treated with AST (25, 50, or 75 mg/kg) 24 h before ischemia/reperfusion surgery. The effects of AST on pathological renal injury in mice after I/R were determined using hematoxylin–eosin staining. HK‐2 cells were pre‐treated with AST (50, 100, or 200 μM) for 24 h before exposure to hypoxia/reoxygenation. The impact of AST on oxidative stress, apoptosis, and pyroptosis, as well as the Sirt1/Nrf2/HO‐1 pathway in vivo and in vitro, was detected. The binding of AST with Sirt1 was verified using molecular docking and cellular thermal shift assay (CETSA). AST ameliorated pathological renal injury, reduced ROS production and MDA levels, increased SOD activity, and inhibited apoptosis and NLRP3‐mediated pyroptosis in mice after I/R. AST attenuated H/R‐induced oxidative stress, apoptosis, and pyroptosis in HK‐2 cells. Mechanically, AST increased the levels of Sirt1, Nrf2, and HO‐1 in the kidneys of mice undergoing I/R and in H/R‐stimulated HK‐2 cells. The inhibition of Sirt1 by EX725 or si‐Sirt1 reversed the protective effects of AST on RIRI. AST exhibits renoprotective effects in RIRI by alleviating oxidative stress‐induced pyroptosis and apoptosis by activating the SIRT1/Nrf2 pathway, suggesting that AST might be a novel therapeutic agent for RIRI.

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