title: Loss of angiotensin-converting enzyme-2 (Ace2) accelerates diabetic kidney injury.
abstract: Diabetic nephropathy is one of the most common causes of end-stage renal failure, but the factors responsible for the development of diabetic nephropathy have not been fully elucidated. We examined the effect of deletion of the angiotensin-convert-ing enzyme 2 (Ace2) gene on diabetic kidney injury. Ace2(-/-) mice were crossed with Akita mice (Ins2(WT/C96Y)), a model of type 1 diabetes mellitus, and four groups of mice were studied at 3 months of age: Ace2(+/y)Ins2(WT/WT), Ace2(-/y)Ins2(WT/WT), Ace2(+/y) Ins2(WT/C96Y), and Ace2(-/y)Ins2(WT/C96Y). Ace2(-/y) Ins2(WT/C96Y) mice exhibited a twofold increase in the urinary albumin excretion rate compared with Ace2(+/y)Ins2(WT/C96Y) mice despite similar blood glucose levels. Ace2(-/y)Ins2(WT/C96Y) mice were the only group to exhibit increased mesangial matrix scores and glomerular basement membrane thicknesses compared with Ace2(+/y)Ins2(WT/WT) mice, accompanied by increased fibronectin and alpha-smooth muscle actin immunostaining in the glomeruli of Ace2(-/y) Ins2(WT/C96Y) mice. There were no differences in blood pressure or heart function to account for the exacerbation of kidney injury. Although kidney levels of angiotensin (Ang) II were not increased in the diabetic mice, treatment with an Ang II receptor blocker reduced urinary albumin excretion rate in Ace2(-/y)Ins2(WT/C96Y) mice, suggesting that acceleration of kidney injury in these mice is Ang II-mediated. We conclude that ACE2 plays a protective role in the diabetic kidney, and ACE2 is an important determinant of diabetic nephropathy.
authors.affiliation: Department of Medicine, Division of Nephrology, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Denise W
authors.initials: DW
authors.lastname: Wong
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
authors.forename: Heather
authors.initials: H
authors.lastname: Reich
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
authors.forename: Joyce
authors.initials: J
authors.lastname: Zhou
authors.forename: Qiao C
authors.initials: QC
authors.lastname: Liu
authors.forename: Peter H
authors.initials: PH
authors.lastname: Backx
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Herzenberg
authors.forename: James W
authors.initials: JW
authors.lastname: Scholey
mesh_terms: D000199:Actins / Q000378:metabolism; D000419:Albuminuria / Q000652:urine; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001485:Basement Membrane / Q000473:pathology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D004452:Echocardiography; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D007150:Immunohistochemistry; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D000077405:Irbesartan; D007668:Kidney / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000737:chemistry; D007703:Peptidyl-Dipeptidase A / Q000235:genetics* / Q000378:metabolism / Q000652:urine; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D000199:Actins; D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D001786:Blood Glucose; D005353:Fibronectins; D007328:Insulin; D012333:RNA, Messenger; D013777:Tetrazoles; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; D000077405:Irbesartan