Astragaloside IV Enhances Mitophagy to Alleviate Renal Ischemia/Reperfusion Injury via PINK1/Parkin Pathway

Astragaloside IV (AS-IV), a primary bioactive component of Astragalus membranaceus (AM). It is very effective in regulating renal diseases. However, the possible underlying mechanism of AS-IV on renoprotection remains unclear. The aim of this study is to find out the regulation mechanism of AS-IV on ischemia/reperfusion injury-induced Acute kidney injury (IRI-AKI). At first, AS-IV was confirmed to significantly alleviate renal dysfunction, inflammation, and renal tubular epithelial cell apoptosis in IRI-AKI mice. Then, it was found that AS-IV alleviated mitochondrial dysfunction and renal tubular epithelial cell injury induced by IRI. Growing evidence has suggested that PINK1/Parkin-mediated mitophagy plays a critical protective role in IRI. Based on this, we hypothesized that AS-IV might exert renoprotective effects through activating the PINK1/Parkin mitophagy pathway. After 3-MA inhibition of autophagy, AS-IV no longer showed its protective effect on HK-2 cells in a hypoxic environment. Through further molecular docking, cell thermal migration, and gene targeted silencing experiments, we confirmed that AS-IV activates the PINK1/Parkin mitophagy pathway and ultimately alleviates IRI-AKI. In summary, all these comprehensive experimental findings indicated that AS-IV can be used as a functional food for the prevention of renal ischemia/reperfusion injury.