Role of angiotensin II and bradykinin in experimental diabetic nephropathy. Functional and structural studies.
We explored the relative roles of the suppression of angiotensin II and the prevention of bradykinin degradation in mediating the renoprotective effects of ACE inhibitors in experimental diabetic nephropathy. Over a 24-week period, we studied male Sprague-Dawley diabetic and control rats and Sprague-Dawley diabetic rats treated with the ACE inhibitor ramipril, the angiotensin II-AT1 receptor antagonist valsartan, the bradykinin-B2 receptor antagonist HOE 140 (icatibant), and a combination of ramipril and icatibant. Serial measurements of urinary albumin excretion, blood pressure, and glycated hemoglobin were performed monthly. After 6 months, the animals were killed for the measurement of kidney weight and the assessment of glomerular ultrastructure. Over 24 weeks, urinary albumin excretion showed a continuous rise in the untreated diabetic rats. Both ramipril and valsartan, which were equihypotensive, prevented the increase in urinary albumin excretion over the whole study period. Icatibant therapy did not attenuate the antialbuminuric effect of the ACE inhibitor, nor did it have any effect as the sole therapy. Diabetes was associated with increased glomerular basement membrane thickness, glomerular volume, and total mesangial volume. Both ACE inhibition and angiotensin II receptor antagonism attenuated the glomerular ultrastructural changes to a similar degree. Icatibant did not attenuate the effects of ramipril on glomerular morphology. ACE inhibitors and angiotensin II-AT1 receptor blockers appear to confer similar benefits in experimental diabetic nephropathy, and bradykinin-B2 receptor blockers do not influence this effect. These findings suggest that the blockade of angiotensin II is the major pathway responsible for renoprotection afforded by ACE inhibition in experimental diabetic nephropathy.
Allen
T J
TJ
Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg West, Australia.
Cao
Z
Z
Youssef
S
S
Hulthen
U L
UL
Cooper
M E
ME
D000419:Albuminuria; D000804:Angiotensin II / Q000737:chemistry* / Q000502:physiology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D001794:Blood Pressure; D001920:Bradykinin / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology / Q000502:physiology*; D065168:Bradykinin Receptor Antagonists; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000517:prevention & control; D007668:Kidney / Q000473:pathology; D007678:Kidney Glomerulus / Q000648:ultrastructure; D008297:Male; D009929:Organ Size; D017257:Ramipril / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000627:therapeutic use; D014633:Valine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000068756:Valsartan
D000806:Angiotensin-Converting Enzyme Inhibitors; D065168:Bradykinin Receptor Antagonists; D013777:Tetrazoles; D000804:Angiotensin II; C065679:icatibant; D000068756:Valsartan; D014633:Valine; D017257:Ramipril; D001920:Bradykinin