Prevention of angiotensin II-mediated renal oxidative stress, inflammation, and fibrosis by angiotensin-converting enzyme 2

Hypertension. 2011 Feb;57(2):314-22. doi: 10.1161/HYPERTENSIONAHA.110.164244. Epub 2010 Dec 28.


Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase capable of metabolizing angiotensin (Ang) II into Ang 1 to 7. We hypothesized that ACE2 is a negative regulator of Ang II signaling and its adverse effects on the kidneys. Ang II infusion (1.5 mg/kg⁻¹/d⁻¹) for 4 days resulted in higher renal Ang II levels and increased nicotinamide adenine dinucleotide phosphate oxidase activity in ACE2 knockout (Ace2(-/y)) mice compared to wild-type mice. Expression of proinflammatory cytokines, interleukin-1β and chemokine (C-C motif) ligand 5, were increased in association with greater activation of extracellular-regulated kinase 1/2 and increase of protein kinase C-α levels. These changes were associated with increased expression of fibrosis-associated genes (α-smooth muscle actin, transforming growth factor-β, procollagen type Iα1) and increased protein levels of collagen I with histological evidence of increased tubulointerstitial fibrosis. Ang II-infused wild-type mice were then treated with recombinant human ACE2 (2 mg/kg⁻¹/d⁻¹, intraperitoneal). Daily treatment with recombinant human ACE2 reduced Ang II-induced pressor response and normalized renal Ang II levels and oxidative stress. These changes were associated with a suppression of Ang II-mediated activation of extracellular-regulated kinase 1/2 and protein kinase C pathway and Ang II-mediated renal fibrosis and T-lymphocyte-mediated inflammation. We conclude that loss of ACE2 enhances renal Ang II levels and Ang II-induced renal oxidative stress, resulting in greater renal injury, whereas recombinant human ACE2 prevents Ang II-induced hypertension, renal oxidative stress, and tubulointerstitial fibrosis. ACE2 is an important negative regulator of Ang II-induced renal disease and enhancing ACE2 action may have therapeutic potential for patients with kidney disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics
  • Actins / metabolism
  • Angiotensin II / metabolism
  • Angiotensin II / pharmacology*
  • Angiotensin-Converting Enzyme 2
  • Animals
  • Blotting, Western
  • Collagen / genetics
  • Collagen / metabolism
  • Cytokines / genetics
  • Cytokines / metabolism
  • Female
  • Fibrosis
  • Gene Expression / drug effects
  • Humans
  • Immunohistochemistry
  • Inflammation / metabolism
  • Inflammation / pathology
  • Kidney / drug effects*
  • Kidney / metabolism
  • Kidney / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Smooth / metabolism
  • NADPH Oxidases / metabolism
  • Oxidative Stress / drug effects*
  • Peptidyl-Dipeptidase A / genetics
  • Peptidyl-Dipeptidase A / metabolism*
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction


  • Actins
  • Cytokines
  • Recombinant Proteins
  • Angiotensin II
  • Collagen
  • NADPH Oxidases
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Ace2 protein, mouse
  • Angiotensin-Converting Enzyme 2