Ferulic Acid Protected from Kidney Ischemia Reperfusion Injury in Mice: Possible Mechanism Through Increasing Adenosine Generation via HIF-1

摘要

Ferulic acid (FA), derived from fruits and vegetables, is well-known as a potent antioxidant of scavenging free radicals. However, the role and underlying mechanism of FA on kidney ischemia reperfusion (I/R) injury are limited. Here, we explored the effects of FA on kidney I/R injury. The kidney I/R injury models were carried out by clamping bilateral pedicles for 35min followed by reperfusion for 24h. Mice were orally pretreated with different doses of FA for three times 24h before I/R. The renal function was assessed by serum creatine (Scr) and blood urea nitrogen (BUN). Kidney histology was examined by hematoxylin and eosin (HE) staining and terminal deoxynucleotidly transferased UTP nick-end labeling (TUNEL) assay. Proinflammatory cytokines, caspase-3 activity, adenosine generation, adenosine signaling molecules, and hypoxia inducible factor-1 alpha (HIF-1) were also detected, respectively. The siHIF-1 adenovirus vectors were in vivo used to inhibit the expression of HIF-1. The results showed that FA significantly attenuated kidney damage in renal I/R-operated mice as indicated by reducing levels of Scr and BUN, ameliorating renal pathological structural changes, and tubular cells apoptosis. Moreover, FA pretreatment inhibited I/R-induced renal proinflammatory cytokines and neutrophils recruitment. Interestingly, the levels of HIF-, CD39, and CD73 mRNA and protein as well as adenosine production were all significantly increased after FA pretreatment in the kidney of I/R-performed mice, and inhibiting HIF- expressionusing siRNA abolished this protection of FA on I/R-induced acute kidney injuryas evidenced by more severe renal damage and reduced adenosine production. Our findings indicated that FA protected against kidney I/R injury by reducing apoptosis, alleviating inflammation, increasing adenosine generation, and upregulating CD39 and CD73 expression, which might be mediated by HIF-1.