Loss of angiotensin-converting enzyme-2 leads to the late development of angiotensin II-dependent glomerulosclerosis.
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.
Oudit
Gavin Y
GY
Rm. 68, 150 College St., Heart and Stroke/Richard Lewar Centre of Excellence, Fitzgerald Bldg., University of Toronto, Toronto M5S 3E2, Canada. gavin.oudit@utoronto.ca
Herzenberg
Andrew M
AM
Kassiri
Zamaneh
Z
Wong
Denise
D
Reich
Heather
H
Khokha
Rama
R
Crackower
Michael A
MA
Backx
Peter H
PH
Penninger
Josef M
JM
Scholey
James W
JW
D000804:Angiotensin II / Q000378:metabolism*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D003094:Collagen / Q000737:chemistry; D004195:Disease Models, Animal; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D005923:Glomerulosclerosis, Focal Segmental / Q000473:pathology*; D007674:Kidney Diseases / Q000473:pathology*; D007678:Kidney Glomerulus / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D007703:Peptidyl-Dipeptidase A / Q000502:physiology*
D005353:Fibronectins; D000804:Angiotensin II; D003094:Collagen; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2