Ischemia-induced brain damage is enhanced in human renin and angiotensinogen double-transgenic mice

Am J Physiol Regul Integr Comp Physiol. 2009 Nov;297(5):R1526-31. doi: 10.1152/ajpregu.91040.2008. Epub 2009 Sep 16.

Abstract

To investigate the role of brain angiotensin II (ANG II) in the pathogenesis of injury following ischemic stroke, mice overexpressing renin and angiotensinogen (R+A+) and their wild-type control animals (R-A-) were used for experimental ischemia studies. Focal brain ischemia was induced by middle cerebral artery occlusion (MCAO). The severity of ischemic injury was determined by measuring neurological deficits and histological damage at 24 and 48 h after MCAO, respectively. To exclude the influence of blood pressure and local collateral blood flow, brain slices were used for oxygen and glucose deprivation (OGD) studies. The severity of OGD-induced damage was determined by measuring indicators of tissue swelling and cell death, the intensity of the intrinsic optical signal (IOS), and the number of propidium iodide (PI) staining cells, respectively. Results showed 1) R+A+ mice showed higher neurological deficit score (3.8 +/- 0.5 and 2.5 +/- 0.3 for R+A+ and R-A-, respectively, P < 0.01) and larger infarct volume (22.2 +/- 1.6% and 14.1 +/- 1.2% for R+A+ and R-A-, respectively, P < 0.01); 2) The R+A+ brain slices showed more severe tissue swelling and cell death in the cortex (IOS: 140 +/- 6% and 114 +/- 10%; PI: 139 +/- 20 cells/field and 39 +/- 9 cells/field for R+A+ and R-A-, respectively, P < 0.01); 3) treatment with losartan (20 micromol/l) abolished OGD-induced exaggeration of cell injury seen in R+A+ mice. The data indicate that activation of ANG II/AT(1) signaling is harmful to brain exposed to ischemia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / metabolism
  • Angiotensin II Type 1 Receptor Blockers / pharmacology
  • Angiotensinogen / genetics
  • Angiotensinogen / metabolism*
  • Animals
  • Blood Pressure / physiology
  • Brain / blood supply
  • Brain / metabolism*
  • Brain / pathology
  • Brain Ischemia / etiology
  • Brain Ischemia / metabolism*
  • Brain Ischemia / pathology
  • Cell Death / physiology
  • Disease Models, Animal
  • Humans
  • Infarction, Middle Cerebral Artery / complications
  • Losartan / pharmacology
  • Male
  • Mice
  • Mice, Transgenic
  • Receptor, Angiotensin, Type 1 / drug effects
  • Receptor, Angiotensin, Type 1 / metabolism
  • Regional Blood Flow / physiology
  • Renin / genetics
  • Renin / metabolism*
  • Severity of Illness Index*
  • Signal Transduction / physiology

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Receptor, Angiotensin, Type 1
  • Angiotensinogen
  • Angiotensin II
  • Renin
  • Losartan