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From the Division of Cardiology,* the Department of Laboratory Medicine and Pathology, and the Division of Nephrology, the Department of Medicine, University Health Network, University of Toronto, Toronto, Canada; the Department of Medical Biophysics, Ontario Cancer Institute, Toronto, Canada; the Merck Frosst Centre for Therapeutic Research,¶ Montreal, Canada; and the Institute for Molecular Biotechnology of the Austrian Academy of Sciences,|| Vienna, Austria
Angiotensin-converting enzyme-2 (ACE2), a membrane-bound carboxymonopeptidase highly expressed in the kidney, functions as a negative regulator of the renin-angiotensin system. Here we report early accumulation of fibrillar collagen in the glomerular mesangium of male ACE2 mutant (ACE2–/y) mice followed by development of glomerulosclerosis by 12 months of age whereas female ACE2 mutant (ACE2–/–) mice were relatively protected. Progressive kidney injury was associated with increased deposition of collagen I, collagen III and fibronectin in the glomeruli and increased urinary albumin excretion compared to age-matched control mice. These structural and functional changes in the glomeruli of male ACE2 mutant mice were prevented by treatment with the angiotensin II type-1 receptor antagonist irbesartan. Loss of ACE2 was associated with a marked increase in renal lipid peroxidation product formation and activation of mitogen-activated protein kinase and extracellular signal-regulated kinases 1 and 2 in glomeruli, events that are also prevented by angiotensin II type-1 receptor blockade. We conclude that deletion of the ACE2 gene leads to the development of angiotensin II-dependent glomerular injury in male mice. These findings have important implications for our understanding of ACE2, the renin-angioten-sin system, and gender in renal injury, with ACE2 likely to be an important therapeutic target in kidney disease.
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