ACE2 deficiency modifies renoprotection afforded by ACE inhibition in experimental diabetes

Chris Tikellis, Katarzyna Bialkowski, Josepha Pete, Karen Sheehy, Qui Su, Colin Johnston, Mark E. Cooper, Merlin C. Thomas

Research output: Contribution to journalArticleResearchpeer-review

140 Citations (Scopus)

Abstract

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 · kg -1 · day-1). Wild-type mice were further randomized to receive the selective ACE2 inhibitor MLN-4760 (10 mg · kg -1 · day-1) 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

Original languageEnglish
Pages (from-to)1018-1025
Number of pages8
JournalDiabetes
Volume57
Issue number4
DOIs
Publication statusPublished - 1 Apr 2008
Externally publishedYes

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