ACE2 deficiency modifies renoprotection afforded by ACE inhibition in experimental diabetes

Abstract Objective: The degradation of angiotensin (Ang) II by angiotensin converting enzyme 2 (ACE2), leading to the formation of Ang 1–7, is an important step in the renin-angiotensin system (RAS), and one which is significantly altered in the diabetic kidney. This study examines the role of ACE2 in early renal changes associated with diabetes, and the influence of ACE2 deficiency on ACE inhibitor-mediated renoprotection. Methods: Streptozotocin diabetes was induced in male c57bl6 mice and ACE2 KO mice. After five weeks of study, animals were randomised to receive the ACE inhibitor, perindopril (2 mg/kg/day). Wild-type mice were further randomised to receive the selective ACE2 inhibitor, MLN-4760 (10 mg/kg/day) and followed for an additional five weeks. Markers of renal function and injury were then assessed. Results: The induction of diabetes in wild-type mice was associated with a reduction in renal ACE2 expression and decreased Ang1-7. In diabetic mice receiving MLN-4760 and in ACE2 KO mice, diabetes-associated albuminuria was enhanced, associated with an increase in blood pressure. However, renal hypertrophy and fibrogenesis were reduced in diabetic mice with ACE2 deficiency and hyperfiltration was attenuated. Diabetic wild type mice treated with an ACE inhibitor experienced a reduction in albuminuria and blood pressure. These responses were attenuated in both diabetic ACE2 KO mice and diabetic mice receiving MLN-4760. However, other renoprotective and antifibrotic actions of ACE inhibition in diabetes were preserved in ACE2 deficient mice. Conclusions: The expression of ACE2 is significantly modified by diabetes, which impacts both on the pathogenesis of kidney disease, as well as the responsiveness to RAS blockade. These data indicate that ACE2 is a complex, and site-specific modulator of diabetic kidney disease.