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

Am J Pathol. 2006 Jun;168(6):1808-20. doi: 10.2353/ajpath.2006.051091.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / metabolism*
  • Angiotensin-Converting Enzyme 2
  • Animals
  • Collagen / chemistry
  • Disease Models, Animal
  • Female
  • Fibronectins / metabolism
  • Glomerulosclerosis, Focal Segmental / pathology*
  • Kidney Diseases / pathology*
  • Kidney Glomerulus / metabolism
  • MAP Kinase Signaling System
  • Male
  • Mice
  • Mice, Transgenic
  • Peptidyl-Dipeptidase A / physiology*


  • Fibronectins
  • Angiotensin II
  • Collagen
  • Peptidyl-Dipeptidase A
  • Ace2 protein, mouse
  • Angiotensin-Converting Enzyme 2