In vivo bradykinin B2 receptor activation reduces renal fibrosis

Abstract

Angiotensin-converting enzyme (ACE) inhibitors reduce the progression of various fibrotic renal diseases both in humans and in animal models. Unilateral ureteral obstruction (UUO) is an animal model of accelerated renal tubulointerstitial fibrosis that is attenuated by ACE inhibition. Although ACE inhibitors increase bradykinin concentrations in addition to their effect on angiotensin II formation, the role of bradykinin in renal fibrosis has not been studied. We show here that genetic ablation (B2(-/-) mice) or pharmacological blockade of the bradykinin B2 receptor increases UUO-induced interstitial fibrosis in mice, whereas transgenic rats expressing increased endogenous bradykinin show reduced UUO-induced interstitial fibrosis. The increased interstitial fibrosis in B2(-/-) mice was accompanied by a decreased activity of plasminogen activators (PAs) and metalloproteinase-2 (MMP-2), enzymes involved in ECM degradation, suggesting that the protective effects of bradykinin involve activation of a B2 receptor/PA/MMP-2 cascade. This ability of bradykinin to increase PA activity was confirmed in primary culture proximal tubular cells. Thus, in both mice and rats, bradykinin B2 receptor activation reduces renal tubulointerstitial fibrosis in vivo, most likely by increasing ECM degradation.

Participation of kallikrein–kinin system in different pathologies

“…Corroborating with that, the B 2 receptor antagonist icatibant abolished the kallikrein's protective effects [48]. The participation of this receptor in the protective effect against renal injury was also evidenced in B 2 receptor knockout mice [49,50]. In addition, a human B 2 receptor gene polymorphism has been demonstrated in patients with chronic renal failure, suggesting a role of this receptor in the early development of this pathology [51].…”

“…The protective role of BK in unilateral renal obstruction was suggested by Morrissey and coworkers [64]; and Schanstra and coworkers using this model in B 2 knockout mice demonstrated that BK has antifibrotic properties [50].…”

The renin-angiotensin system and its blockade in diabetic renal and cardiovascular disease

“…As mentioned earlier, ACEIs increase bradykinin levels, which have antihypertensive and possibly antifibrotic properties [15,22,23] and are responsible for the side effects of ACEIs. Occurrence of Ang II escape, on the other hand, makes the blockade of RAAS with ACEIs potentially less complete over time.…”

Deletion of bradykinin B1 receptor reduces renal fibrosis

“…Schanstra and colleagues had demonstrated that increased endogenous bradykinin levels lowered renal fibrosis in UUO and that B2R deletion enhanced this process, postulating that bradykinin anti-fibrotic role was B2R dependent [15]. Conversely, when B2KO mice were treated with ACE inhibitors they showed reduced fibrosis, indicating that the anti-fibrotic effects achieved under ACE-inhibition were independent of B2R activation [24].…”

“…In UUO, bradykinin overexpression reduced tubulointerstitial fibrosis and in vivo B2R deletion was deleterious [15]. Thus, it is believed that bradykinin may be anti-fibrotic via B2R activation.…”