Pharmacological blockade of B2-kinin receptor reduces renal protective effect of angiotensin-converting enzyme inhibition in db/db mice model

1 Laboratoire de Physiologie, Faculté de Médecine Rangueil, Toulouse; 2 Institut National de la Santé et de la Recherche Médicale, Unité 858, Toulouse; and 3 Université Toulouse III Paul-Sabatier, Institut de Médecine Moléculaire de Rangueil, Equipe 5, IFR31, Toulouse, France Submitted 25 October 2007 ; accepted in final form 12 March 2008 Diabetic nephropathy (DN) can be delayed by the use of angiotensin-converting enzyme inhibitors (ACEi). The mechanisms of ACEi renal protection are not univocal. To investigate the impact of bradykinin B 2 receptor (B2R) activation during ACE inhibition, type II diabetic mice (C57BLKS db/db ) received for 20 wk: 1 ) ACEi (ramipril) alone, 2 ) ACEi + HOE-140 (a specific B2R antagonist), 3 ) HOE-140 alone, or 4 ) no treatment. The development of DN, defined by an increase in albuminuria and glomerulosclerosis, was largely prevented by ACEi treatment (albuminuria: 980 ± 130 vs. 2,160 ± 330 mg/g creatinine; mesangial area: 22.5 ± 0.5 vs. 27.6 ± 0.3%). The protective effect of ramipril was markedly attenuated by B2R blockade (albuminuria: 2,790 ± 680 mg/g creatinine; mesangial area: 30.4 ± 1.1%), whereas HOE-140 alone significantly increased albuminuria. Despite such benefits, glomerular filtration rate remained unchanged, probably because of the combination of the hypotensive effect of diabetes in this model and the renal hemodynamic action of ramipril. Finally, the renal protective effect of ACEi was associated with a marked decrease in glomerular overexpression of insulin-like growth factor-1 (IGF-1) and transforming growth factor-β pathways, but also in advanced glycation end product receptors and lipid peroxidation assessed by 4-hydroxy-2-nonenal (4-HNE) adducts. Concomitant blockade of B2R partly restored glomerular overexpression of IGF-1 receptor β and 4-HNE complexes. These results support the critical role of B2R activation in the mediation of ACEi renal protection against DN and provide the rationale to examine the benefit of B2R activation by itself as a new therapeutic approach for DN. angiotensin-converting enzyme inhibitors; bradykinin; glomerulopathy Address for reprint requests and other correspondence: I. Tack, INSERM U858 eq 5 BP 84, Institut Louis Bugnard, BP 84225, 31432 Toulouse Cedex 4, France (e-mail: tack.i{at}chu-toulouse.fr )