Reduced renal vascular ACE activity in diabetes

Our previous work supports a major role for ACE‐independent intrarenal ANG II formation on microvascular function in type II diabetes ( db/db mouse). Studies were conducted to test the hypothesis that ACE plays a minor role, whereas chymase plays a major role in intrarenal ANG II formation in diabetes. Afferent arteriole (AA) diameter responses to the intrarenal conversion of an ACE‐specific, chymase‐resistant ANG I analogue ([Pro 10 ]ANG I) to ANG II were significantly enhanced in control compared to diabetic kidneys. AA diameters were significantly reduced by 12±2, 18±5, and 16±4% (10–1000nM [Pro 10 ]ANG I) in control kidneys (n=7; p<0.05), but not in diabetic kidneys (n= 9). AA vasoconstrictor responses to a chymase‐specific, ACE‐resistant ANG I analogue ([Pro 11 , DAla 12 ]ANG I) were significantly enhanced in diabetic compared to control kidneys. AA diameters were reduced by 9±2, 15±3, and 24±3% in diabetic kidneys (10–1000nM [Pro 11 , DAla 12 ]ANG I; n=8; p<0.05), but not in control kidneys. [Pro 11 , DAla 12 ]ANG I AA responses were significantly attenuated by a chymase‐specific inhibitor [Suc‐Val‐Pro‐Phe P (OPh) 2 ; 0.1mM intraluminal] in diabetic kidneys (n=6). In summary, diabetic kidneys exhibit a lack of ACE activity and heightened chymase activity compared to control. Chymase may serve as a new target for reducing diabetic renal vascular disease. Funding NIDDK & AHA