OBJECTIVE-The degradation of angiotensin (Ang) II by ACE2, leading to the formation of Ang 1-7, is an important step in the renin-angiotensin system (RAS) and one that 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.RESEARCH DESIGN AND METHODS-Diabetes was induced by streptozotocin in male c57bl6 mice and ACE2 knockout (KO) mice. After 5 weeks of study, animals were randomized to receive the ACE inhibitor perindopril (2 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ). Wild-type mice were further randomized to receive the selective ACE2 inhibitor MLN-4760 (10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) and followed for an additional 5 weeks. Markers of renal function and injury were then assessed.RESULTS-Induction of diabetes in wild-type mice was associated with a reduction in renal ACE2 expression and decreased Ang 1-7. 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 pathogenesis of kidney disease and responsiveness to RAS blockade. These data indicate that ACE2 is a complex and site-specific modulator of diabetic kidney disease.

A diet high in fat induces cardiac hypertrophy, inflammation, and oxidative stress. Although such actions have largely been ascribed to fat deposition, the accumulation of advanced glycation end products (AGEs) and subsequent activation of the receptor for AGEs (RAGE) may also represent important mediators of cardiac injury following exposure to a Western diet. In this study, male C57BL6J and RAGE knockout mice were placed on either a standard diet (7% fat) or a Western "fast-food" diet (21% fat). Animals receiving a high-fat diet were further randomized to receive the AGE inhibitor alagebrium chloride (1 mg.kg(-1).day(-1)) and followed for 16 wk. A Western diet was associated with cardiac hypertrophy, inflammation, mitochondrial-dependent superoxide production, and cardiac AGE accumulation in wild-type mice. Although RAGE-KO mice fed a Western diet also became obese and accumulated intramyocardial lipid, cardiomyocyte hypertrophy, inflammation, and oxidative stress were attenuated compared with wild-type mice. Similarly, mice of both strains receiving alagebrium chloride had reduced levels of inflammation and oxidative stress, in association with a reduction in cardiac AGEs and RAGE. This study suggests that AGEs represent important mediators of cardiac injury associated with a Western fast-food diet. These data point to the potential utility of AGE-reducing strategies in the prevention and management of cardiac disease.