Major role for ACE-independent intrarenal ANG II formation in type II diabetes.
Combination therapy of angiotensin-converting enzyme (ACE) inhibition and AT(1) receptor blockade has been shown to provide greater renoprotection than ACE inhibitor alone in human diabetic nephropathy, suggesting that ACE-independent pathways for ANG II formation are of major significance in disease progression. Studies were performed to determine the magnitude of intrarenal ACE-independent formation of ANG II in type II diabetes. Although renal cortical ACE protein activity [2.1 +/- 0.8 vs. 9.2 +/- 2.1 arbitrary fluorescence units (AFU) x mg(-1) x min(-1)] and intensity of immunohistochemical staining were significantly reduced and ACE2 protein activity (16.7 +/- 3.2 vs. 7.2 +/- 2.4 AFU x mg(-1) x min(-1)) and intensity elevated, kidney ANG I (113 +/- 24 vs. 110 +/- 45 fmol/g) and ANG II (1,017 +/- 165 vs. 788 +/- 99 fmol/g) levels were not different between diabetic and control mice. Afferent arteriole vasoconstriction due to conversion of ANG I to ANG II was similar in magnitude in kidneys of diabetic (-28 +/- 3% at 1 microM) and control (-23 +/- 3% at 1 microM) mice; a response completely inhibited by AT(1) receptor blockade. In control kidneys, afferent arteriole vasoconstriction produced by ANG I was significantly attenuated by ACE inhibition, but not by serine protease inhibition. In contrast, afferent arteriole vasoconstriction produced by intrarenal conversion of ANG I to ANG II was significantly attenuated by serine protease inhibition, but not by ACE inhibition in diabetic kidneys. In conclusion, there is a switch from ACE-dependent to serine protease-dependent ANG II formation in the type II diabetic kidney. Pharmacological targeting of these serine protease-dependent pathways may provide further protection from diabetic renal vascular disease.
Sungmi
S
Park
Benjamin J
BJ
Bivona
Hiroyuki
H
Kobori
Dale M
DM
Seth
Mark C
MC
Chappell
Eric
E
Lazartigues
Lisa M
LM
Harrison-Bernard
D000803:Angiotensin I / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism*; D000085962:Angiotensin-Converting Enzyme 2; D000808:Angiotensinogen / Q000652:urine; D000818:Animals; D001160:Arterioles / Q000473:pathology / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D003925:Diabetic Angiopathies / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D007668:Kidney / Q000098:blood supply / Q000378:metabolism*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D054411:Receptors, Leptin / Q000235:genetics; D057057:Serine Proteases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014661:Vasoconstriction / Q000502:physiology
D054411:Receptors, Leptin; D000808:Angiotensinogen; D000804:Angiotensin II; D000803:Angiotensin I; D057057:Serine Proteases; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2