In vivo bradykinin B2 receptor activation reduces renal fibrosis.
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.
Schanstra
Joost P
JP
Inserm U388, Institut Louis Bugnard, Toulouse, France.
Neau
Eric
E
Drogoz
Pascale
P
Arevalo Gomez
Miguel A
MA
Lopez Novoa
José Miguel
JM
Calise
Denis
D
Pecher
Christiane
C
Bader
Michael
M
Girolami
Jean-Pierre
JP
Bascands
Jean-Loup
JL
D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002455:Cell Division; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005355:Fibrosis / Q000473:pathology; D007124:Immunoenzyme Techniques; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009395:Nephritis, Interstitial / Q000473:pathology*; D010960:Plasminogen Activators / Q000378:metabolism; D051381:Rats; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D020840:Tissue Kallikreins / Q000235:genetics; D014517:Ureteral Obstruction / Q000473:pathology*
D016326:Extracellular Matrix Proteins; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; C065679:icatibant; D003094:Collagen; D010960:Plasminogen Activators; D020840:Tissue Kallikreins; D020778:Matrix Metalloproteinase 2; D001920:Bradykinin