Abstract
Previously we have demonstrated that bradykinin B1 receptor deficient mice (B1KO) were protected against renal ischemia and reperfusion injury (IRI). Here, we aimed to analyze the effect of B1 antagonism on renal IRI and to study whether B1R knockout or antagonism could modulate the renal expression of pro and anti-inflammatory molecules. To this end, mice were subjected to 45 minutes ischemia and reperfused at 4, 24, 48 and 120 hours. Wild-type mice were treated intra-peritoneally with antagonists of either B1 (R-954, 200 µg/kg) or B2 receptor (HOE140, 200 µg/kg) 30 minutes prior to ischemia. Blood samples were collected to ascertain serum creatinine level, and kidneys were harvested for gene transcript analyses by real-time PCR. Herein, B1R antagonism (R-954) was able to decrease serum creatinine levels, whereas B2R antagonism had no effect. The protection seen under B1R deletion or antagonism was associated with an increased expression of GATA-3, IL-4 and IL-10 and a decreased T-bet and IL-1β transcription. Moreover, treatment with R-954 resulted in lower MCP-1, and higher HO-1 expression. Our results demonstrated that bradykinin B1R antagonism is beneficial in renal IRI.
Highlights
Renal ischemia and reperfusion injury (IRI) is a leading cause of acute renal failure in both allografts and native kidneys [1]
A previous study by our group demonstrated that bradykinin receptors may influence tissue outcome in renal IRI [27]
Cross-modulation has been previously described in different experimental models of intestinal [28], cardiac [29,30,31] and renal [31,32] insults
Summary
Renal ischemia and reperfusion injury (IRI) is a leading cause of acute renal failure in both allografts and native kidneys [1]. Inflammation plays an important role in the pathogenesis of renal IRI, through leukocyte activation and expression of adhesion molecules and cytokines [2,3,4,5,6,7,8]. Bradykinin receptor activation may affect this inflammatory response. Physiological effects of bradykinin are mediated by two transmembrane G-coupled proteins, namely B1 and B2 receptors (B1R and B2R, respectively) [9]. B2R is constitutively expressed under physiological conditions and is responsible for most kinin effects [9]. Several studies have shown that B1R can influence immune responses by modulating T lymphocytes [13,14] and leukocyte migration [14,15] and prostaglandins [16], mast cell mediators [17], cytokines [18,19] and chemokines production [20,21,22]
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