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Am J Pathol. 2006 Jun;168(6):1808-20.

Loss of angiotensin-converting enzyme-2 leads to the late development of angiotensin II-dependent glomerulosclerosis.

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  • 1Rm. 68, 150 College St., Heart and Stroke/Richard Lewar Centre of Excellence, Fitzgerald Bldg., University of Toronto, Toronto M5S 3E2, Canada.


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-angiotensin system, and gender in renal injury, with ACE2 likely to be an important therapeutic target in kidney disease.

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