Pharmacological blockade of B2-kinin receptor reduces renal protective effect of angiotensin-converting enzyme inhibition in db/db mice model.
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-beta 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 beta 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.
Buléon
Marie
M
Laboratoire de Physiologie, Faculté de Médecine Rangueil, Toulouse, France.
Allard
Julien
J
Jaafar
Acil
A
Praddaude
Françoise
F
Dickson
Zara
Z
Ranera
Marie-Thérèse
MT
Pecher
Christiane
C
Girolami
Jean-Pierre
JP
Tack
Ivan
I
D000419:Albuminuria / Q000517:prevention & control; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D065094:Bradykinin B2 Receptor Antagonists; D003929:Diabetic Neuropathies / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D005919:Glomerular Filtration Rate; D007668:Kidney / Q000473:pathology; D007677:Kidney Function Tests; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D020011:Protective Agents / Q000494:pharmacology*; D017257:Ramipril / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D065094:Bradykinin B2 Receptor Antagonists; D020011:Protective Agents; C065679:icatibant; D017257:Ramipril; D001920:Bradykinin