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).


CONCLUSIONS
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.
Seccia
Teresa M
TM
Department of Clinical Methodology, University of Bari, Italy.
Belloni
Anna S
AS
Guidolin
Diego
D
Sticchi
Daniele
D
Nussdorfer
Gastone G
GG
Pessina
Achille C
AC
Rossi
Gian Paolo
GP
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D030801:Animals, Genetically Modified; D009320:Atrial Natriuretic Factor / Q000187:drug effects; D001552:Benzazepines / Q000494:pharmacology*; D003404:Creatinine / Q000097:blood; D005355:Fibrosis / Q000517:prevention & control; D006973:Hypertension / Q000188:drug therapy; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology*; D017257:Ramipril / Q000494:pharmacology*; D051381:Rats; D043782:Receptor, Bradykinin B2 / Q000502:physiology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D011725:Pyridines; D043782:Receptor, Bradykinin B2; C085683:MDL 100240; D009320:Atrial Natriuretic Factor; D003404:Creatinine; D015260:Neprilysin; D017257:Ramipril