Key result
Bradykinin B2 receptor activation reduces renal tubulointerstitial fibrosis by enhancing extracellular matrix degradation.
Why the study?
The role of bradykinin in renal fibrosis had not been studied despite ACE inhibitors increasing bradykinin concentrations and reducing renal fibrosis.
Bradykinin B2 receptor activation reduces renal tubulointerstitial fibrosis in vivo, likely by increasing extracellular matrix degradation via the PA/MMP-2 cascade.
Does not support changing ACE inhibitor use based on bradykinin ablation in rodents; leaves open its contribution to antifibrotic effects in patients.
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.
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Schanstra et al. (2002) studied Renal tubulointerstitial fibrosis. Bradykinin B2 receptor activation vs. Wild-type or non-transgenic controls was evaluated on Interstitial fibrosis. In mice and rats, bradykinin B2 receptor activation reduces unilateral ureteral obstruction-induced renal tubulointerstitial fibrosis in vivo, likely by increasing extracellular matrix degradation.
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