Bradykinin B1 and B2 receptors both have protective roles in renal ischemia/reperfusion injury

Abstract

To explore the role of the kallikrein-kinin system in relation to ischemia/reperfusion injury in the kidney, we generated mice lacking both the bradykinin B1 and B2 receptor genes (B1RB2R-null, Bdkrb1 ؊/ ؊/Bdkrb2 ؊/؊ ) by deleting the genomic region encoding the two receptors. In 4-month-old mice, blood pressures were not significantly different among B1RB2R-null, B2R-null (Bdkrb2 ؊/؊ ), and WT mice. After 30 min of bilateral renal artery occlusion and 24 h of reperfusion, mortality rates, renal histological and functional changes, 8-hydroxy-2 -deoxyguanosine levels in total DNA, mtDNA deletions, and the number of TUNEL-positive cells in the kidneys increased progressively in the following order (from lowest to highest): WT, B2R-null, and B1RB2R-null mice. Increases in mRNA levels of TGF-␤1, connective tissue growth factor, and endothelin-1 after ischemia/reperfusion injury were also exaggerated in the same order (from lowest to highest): WT, B2R-null, and B1RB2R-null. Thus, both the B1 and B2 bradykinin receptors play an important role in reducing DNA damage, apoptosis, morphological and functional kidney changes, and mortality during renal ischemia/reperfusion injury.hypoxia ͉ mitochondria ͉ oxidative stress I schemic tissue injuries, including stroke, myocardial infarction, and ischemic acute renal failure, are devastating complications in patients with hypertension, diabetes, atherosclerosis, and senescence. In organ transplantation, damage to allografts during any ischemic period before the transplant markedly influences short-term and long-term graft function and outcome (1). Furthermore, although reoxygenation after ischemia is essential for cell survival, damage also develops during the reperfusion period. Previous studies have shown that acute ATP depletion, intracellular Ca 2ϩ accumulation, and increased generation of reactive oxygen species by mitochondria all play important roles in the pathogenesis of ischemia/reperfusion (I/R) injury (2).Angiotensin-I-converting enzyme (ACE) inhibitors (ACEIs) reduce not only chronic cardiovascular remodeling after ischemia but also acute tissue injury caused by I/R in the heart (3), lung (4), liver (5), and kidneys (6, 7). Several observations indicate that the beneficial effects of ACEIs in the acute phase are mainly due to activation of the bradykinin nitric oxide (NO) cascade as a result of inhibition of the inactivation of bradykinin, rather than due to suppression of angiotensin II formation. Thus, ACEIs are much more effective than angiotensin type I receptor antagonists in protecting against I/R (8-10), and bradykinin B2 receptor (B2R) antagonists and NO synthase blockers markedly attenuate the protective effects of ACEIs (8, 9, 11).Bradykinin and lysyl-bradykinin (kallidin) are generated from kininogens by the kallikreins and some other serine proteases. ACE, which is a carboxydipeptidase, inactivates both peptides by removing two amino acids from their carboxyl termini. In mammals, at least two receptors have been identified: the bradykinin B1 receptor (B...

Lack of both bradykinin B1 and B2 receptors enhances nephropathy, neuropathy, and bone mineral loss in Akita diabetic mice

“…The kinins, acting through B2R also increase the expression of inducible NOS (iNOS) (39). Our previous finding that preprandial levels of plasma nitrite/nitrate are lower in BRKO mice than in WT (23), and another report showing that urinary nitrite/nitrate excretion in B2R-null mice is lower than in WT (40) suggest that the KKS is also important in basal NO production.…”

“…Mice lacking B2R gene or having the diabetogenic Akita mutation (C96Y) in the insulin 2 gene of the C57BL/6 strain were purchased from Jackson Laboratory. Mice lacking both B1R and B2R of a pure C57BL/6 background were generated as previously described (23). All experiments were approved by the University of North Carolina Institutional Animal Care and Use Committee.…”

“…Because the loci coding for B1R and B2R are only 11 kb apart, it is impractical to make mice lacking both B1R and B2R by simply crossbreeding B1R-null mice and B2R-null mice. Consequently, to unambiguously explore the role of KKS, we have generated mice lacking both receptors (BRKO) by deleting the genomic region that includes both genes (23). (There are no identified or predicted ORFs between the loci for B1R and B2R.)…”

Kinin B2receptor does not exert renoprotective effects on mice with glycerol-induced rhabdomyolysis

“…Recent studies [28][29][30][31] show that deletion of B1R and B2R exacerbates the renal phenotype in diabetic mouse models, suggesting that both receptors have a protective effect on diabetic nephropathy by suppressing oxidative stress via NO and prostaglandins. However, because the absence of one of the receptors causes increased expression of the other, it is difficult to determine the precise function of each receptor [28] .…”

“…Kinin receptors in renal tissue were studied in the I/R model, where it was shown that both receptors have a protective role in this type of injury [30] . However, a different study [15] found that during I/R in mice, the double knockout showed an extremely high SCr along with a proinflammatory profile.…”