Published online before print June 28, 2007

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(American Journal of Pathology. 2007;171:438-451.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060977

Loss of Angiotensin-Converting Enzyme-2 (Ace2) Accelerates Diabetic Kidney Injury

Denise W. Wong^*, Gavin Y. Oudit, Heather Reich^*, Zamaneh Kassiri, Joyce Zhou^*, Qiao C. Liu^*, Peter H. Backx, Josef M. Penninger, Andrew M. Herzenberg^¶ and James W. Scholey^*

From the Department of Medicine,^* Division of Nephrology, University Health Network, University of Toronto, Toronto, Ontario, Canada; the Department of Medicine, Division of Cardiology, and the Department of Medical Biophysics, Ontario Cancer Institute, Toronto, Ontario, Canada; and the Departments of Medical Biophysics and Laboratory Medicine and Pathology,^¶ University of Toronto, Toronto, Ontario, Canada; and MBA, Institute for Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria

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^+/yIns2^WT/WT, Ace2^–/yIns2^WT/WT, Ace2^+/y Ins2^WT/C96Y, and Ace2^–/yIns2^WT/C96Y. Ace2^–/y Ins2^WT/C96Y mice exhibited a twofold increase in the urinary albumin excretion rate compared with Ace2^+/yIns2^WT/C96Y mice despite similar blood glucose levels. Ace2^–/yIns2^WT/C96Y mice were the only group to exhibit increased mesangial matrix scores and glomerular basement membrane thicknesses compared with Ace2^+/yIns2^WT/WT mice, accompanied by increased fibronectin and -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^–/yIns2^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.

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