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

Abstract

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 35 min followed by reperfusion for 24 h. Mice were orally pretreated with different doses of FA for three times 24 h 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-1α) were also detected, respectively. The siHIF-1α adenovirus vectors were in vivo used to inhibit the expression of HIF-1α. 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-α, 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-α expression using siRNA abolished this protection of FA on I/R-induced acute kidney injury as 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-1α.

The Effects and Mechanisms of Cyanidin-3-Glucoside and Its Phenolic Metabolites in Maintaining Intestinal Integrity

“…Anti-inflammatory HUVEC cells, mice, rats FA decreased the expression of caspase-1 [52], ICAM-1 [52], VCAM-1 [52], IL-18 [52], IL-1β [50,[52][53][54], IL-6 [50,54], TNF-α [53], and inhibited the phosphorylation of p38 and IκB [52].…”

“…Additionally, VA can inhibit the production of pro-inflammatory cytokines such as TNF-α, IL-6, IL-1β, and IL-33 by down-regulating caspase-1 and NF-κB pathways [45][46][47] in mice or mouse peritoneal macrophages and mast cells. FA has also been reported to attenuate both oxidative stress and inflammation potentially by suppressing the production of free radicals (ROS and NO in rats, rat intestinal mucosal IEC-6 cell, or murine macrophages) [48][49][50], enhancing Nrf2 expression and down-stream antioxidant enzymes (SOD and CAT in rats or swiss albino mice) [48,51], and inhibiting the activation of proinflammatory proteins (p38 and IκB in HUVEC cells) [52] and cytokines production, such as IL-18 in HUVEC cells [52], IL-1β in mice [53], IL-6 in obese rats [54], and TNF-α in mice [53]. However, both VA and FA showed a limited effect on the activation of MAPK pathway and production of inflammatory cytokines, such as monocyte chemoattractant protein-1 (MCP-1) and TNF-α in a high-fat diet-induced mouse model of nonalcoholic fatty liver disease [41].…”

Ferulic acid attenuates microglia-mediated neuroinflammation in retinal degeneration

“…Ferulic acid (FA), phenol compound present in the wall of plants, is a major active ingredient in some traditional Chinese medicine(TCM), such as ferula asafetida, angelica, ligusticumwallichii, which are always used to improve microcirculation of ischemic diseases in TCM prescription [9,10]. Nowadays, a growing body of research findings demonstrated that FA suppressed detrimental immunoreactions under various conditions.…”

Ferulic acid attenuates microglia-mediated neuroinflammation in retinal degeneration

“…Ferulic acid (FA), phenol compound present in the wall of plants, is a major active ingredient in some traditional Chinese medicine(TCM), such as ferula asafetida, angelica, ligusticumwallichii, which always used to improve microcirculation of ischemic diseases in TCM prescription [8,9]. Nowadays, a growing body of research demonstrated that FA suppressed detrimental immunoreactions under various conditions.…”