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

The renoprotective action of angiotensin I converting enzyme-inhibitors (ACE-I) is well es-tablished, but the role played by bradykinin (BK) remains uncertain. We therefore investi-gated whether enhanced BK effect on B2 receptor subtype mediated the antifibrotic effect of ACE-I and if NEP-inhibition, which can blunt more effectively BK degradation than ACE-inhibition, provided further renoprotection in a rat model of Ang II-dependent renal dam-age. Five-week-old Ren-2 transgenic rats (TGRen2) received for 8 weeks a placebo, ramipril (5 mg.Kg-1. b.w.-1) or the dual ACE+NEP inhibitor MDL 100,240 (MDL) (40 mg.Kg-1 . b.w.-1). After 4 weeks, the B2 receptor antagonist icatibant (0.5 mg.Kg-1. b.w.-1) was administered on top of active treatment for 4 weeks to 50% of TGRen2. Blood pressure was measured weekly by a tail-cuff method and, after sacrifice, kidney weight, glomerular volume, density of glomerular profiles, tubulo-interstitial fibrosis, glomerular and perivascular fibrosis were quantified by histo-morphometry. Both ramipril and MDL prevented the development of hypertension and tubulo-interstitial (p=0.0001, vs placebo for both); icatibant annulled the latter effect. Glomerular and perivas-cular fibrosis were unaffected by ramipril or MDL alone; however, icatibant on top of either drug (p=0.0001 vs placebo) enhanced glomerular fibrosis. The prevention of tubulo-interstitial with ACE-I or dual ACE+NEP-inhibition involves en-hanced BK effect on B2 subtype receptors in TGRen2.