The renal antifibrotic effects of angiotensin-converting enzyme inhibition involve bradykinin B2 receptor activation in angiotensin II-dependent hypertension

OBJECTIVE: The renoprotective action of angiotensin I-converting enzyme inhibitors (ACE-Is) is well established, but the role played by bradykinin (BK) remains unclear. We therefore investigated whether an enhanced BK effect on B2 receptor subtype mediated the antifibrotic effect of ACE-Is and whether neutral endopeptidase (NEP) inhibition, which can blunt BK degradation more effectively than ACE inhibition, provided further renoprotection in a rat model of angiotensin (Ang) II-dependent renal damage. METHODS: Five-week-old Ren-2 transgenic rats (TGRen2) received, for 8 weeks, a placebo, ramipril (5 mg/kg body weight) or the dual ACE + NEP inhibitor MDL 100,240 (MDL) (40 mg/kg body weight). After 4 weeks, the B2 receptor antagonist icatibant (0.5 mg/kg body weight) was administered on top of active treatment for 4 weeks to 50% of the TGRen2 rats. Blood pressure was measured weekly by a tail-cuff method and, after sacrifice, kidney weight, glomerular volume, density of glomerular profiles were measured; tubulo-interstitial fibrosis, glomerular and perivascular fibrosis were quantified by histomorphometry. RESULTS: The development of hypertension and tubulo-interstitial fibrosis was prevented by both ramipril and MDL (P = 0.0001 versus placebo); icatibant annulled the latter effect. Glomerular and perivascular fibrosis were unaffected by either ramipril or MDL alone; however, combined treatment with icatibant enhanced glomerular fibrosis (P = 0.0001 versus placebo). CONCLUSION: Enhanced BK effect on B2 subtype receptors is essential for the prevention of tubulo-interstitial fibrosis with ACE or dual ACE + NEP inhibition in TGRen2 rats.