Loss of Angiotensin-Converting Enzyme-2 Leads to the Late Development of Angiotensin II-Dependent Glomerulosclerosis

Oudit, Gavin Y.; Herzenberg, Andrew M.; Kassiri, Zamaneh; Wong, Denise; Reich, Heather; Khokha, Rama; Crackower, Michael A.; Backx, Peter H.; Penninger, Josef M.; Scholey, James W.

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.