Submitted on October 25, 2007
Accepted on March 12, 2008
Pharmacological blockade of B2-kinin receptor reduces renal protective effect of Angiotensin-Converting Enzyme Inhibition in db/db mice model
Marie Buleon1, Julien Allard1, Acil Jaafar1, Francoise Praddaude, Zara Dickson2, Marie-Therese Ranera, Christiane Pecher, Jean-Pierre Girolami3, and Ivan Tack1*
1 Laboratoire de Physiologie, Faculte de Medecine Rangueil, Toulouse, France; U858, Institut National de la Sante et de la Recherche Medicale (INSERM), Toulouse, France; Eq n5, IFR31, Universite Toulouse III Paul-Sabatier, Institut de Medecine Moleculaire de Rangueil, Toulouse, France
2 Laboratoire de Physiologie, Faculte de Medecine Rangueil, Toulouse, France; Eq n5, IFR31, Universite Toulouse III Paul-Sabatier, Institut de Medecine Moleculaire de Rangueil, Toulouse, France
3 U858, Institut National de la Sante et de la Recherche Medicale (INSERM), France; Eq n5, IFR31, Universite Toulouse III Paul-Sabatier, Institut de Medecine Moleculaire de Rangueil, France
* To whom correspondence should be addressed. E-mail: tack.i{at}chu-toulouse.fr.
Diabetic nephropathy (DN) can be delayed by the use of Angiotensin converting enzyme inhibitors (ACEi). The mechanisms of ACEi renal protection are not univocal.
In order to investigate the impact of bradykinin B2 receptor (B2R) activation during ACEi, type II diabetic mice (C57BLKs db/db) received for 20 weeks: 1) ACEi (ramipril) alone; 2) ACEi + HOE-140 (a specific B2R antagonist); 3) HOE-140 alone; 4) no treatment.
The development of DN, defined by an increase in albuminuria and glomerulosclerosis was largely prevented by ACEi treatment (albuminuria 980 ± 130 versus 2160 ± 330 mg/g creatinine, mesangial area 22.5 ± 0.5 versus 27.6 ± 0.3 %). The protective effect of ramipril was markedly attenuated by B2R blockade (albuminuria 2790 ± 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 IGF-1 and TGF
pathways, but also in Advanced Glycation End Product receptors and lipid peroxidation assessed by 4-HNE adducts. Concomitant blockade of B2R partly restored glomerular overexpression of IGF-1 R, 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.
