Abstract 12512: Brain Renin is Involved in Chronic Cerebral Hypoperfusion-induced Brain Injury and Cognitive Impairment
Introduction: It remains largely unknown whether brain renin is involved in cognitive dysfunction. We hypothesized that brain renin is involved in vascular dementia and related brain injuries, and renin inhibition might improve these abnormalities.
Methods: (Experiment I) Vascular dementia in mice was induced by bilateral common carotid artery stenosis (BCAS) resulting in chronic cerebral hypoperfusion. C57BL/6J mice with BCAS were treated with (1) vehicle (saline) and (2) direct renin inhibitor (aliskiren, 2.5 mg/kg/day) to investigate the role of brain renin in vascular dementia. (Experiment II) Tempol (1 mmol/L), a superoxide dismutase mimetic, was administrated to C57BL/6J mice with BCAS to examine the role of brain oxidative stress in vascular dementia.
Results: BCAS induced a significant increase of brain angiotensinogen expression and brain renin activity in mice, which was attributed to an increased angiotensinogen in astrocytes and an increased renin in microvessels and astrocytes in brain white matters (WM). Renin inhibition with aliskiren significantly decreased brain renin activity, glial activation, brain MCP-1 and TNF-α expressions in BCAS mice. Furthermore, aliskiren treatment significantly attenuated WM lesions and spatial working memory impairment (Y-maze) in BCAS mice, which was associated with a significant decrease of brain nitrotyrosine being attributed to a significant inhibitory effect of aliskiren on brain NADPH oxidase activity, NADPH subunit p67phox, nitric oxide production and nNOS expression. Therefore, it indicated a potential involvement of brain oxidative stress in aliskiren-associated protective effect. To confirm this assumption, we examined the effect of tempol administration and found that attenuation of brain nitrotyrosine with tempol significantly improved brain WM lesions and spatial working memory in BCAS mice.
Conclusions: Brain renin was involved in chronic cerebral hypoperfusion-induced vascular dementia and related brain injuries. Renin inhibition ameliorated these abnormalities by attenuating NADPH oxidase-mediated brain oxidative stress. Thus, renin inhibition might be a hopeful therapeutic strategy for hypoperfusion-induced brain injury and cognitive impairment.
- © 2011 by American Heart Association, Inc.