RRC ID 11801
Author Inaba S, Iwai M, Furuno M, Tomono Y, Kanno H, Senba I, Okayama H, Mogi M, Higaki J, Horiuchi M.
Title Continuous activation of renin-angiotensin system impairs cognitive function in renin/angiotensinogen transgenic mice.
Journal Hypertension
Abstract We examined the possibility that continuous activation of the human brain renin-angiotensin system causes cognitive impairment, using human renin (hRN) and human angiotensinogen (hANG) gene chimeric transgenic (Tg) mice. Cognitive function was evaluated by the shuttle avoidance test once a week from 10 to 20 weeks of age. The avoidance rate in wild-type mice gradually increased. In contrast, the avoidance rate in chimeric hRN/hANG-Tg mice also increased; however, no further increase in avoidance rate was observed from 14 weeks of age, and it decreased thereafter. Cerebral surface blood flow was markedly reduced in 20-week-old hRN/hANG-Tg mice. Superoxide anion production in the brain was already higher in 10-week-old hRN/hANG-Tg mice and further increased thereafter with an increase in NADPH oxidase activity. Moreover, expression of p47(phox) and Nox4 in the brain of hRN/hANG-Tg mice also increased. Administration of an angiotensin II type 1 receptor blocker, olmesartan (5.0 mg/kg per day), attenuated the increase in blood pressure and ameliorated cognitive decline with enhancement of cerebral surface blood flow and a reduction of oxidative stress in hRN/hANG-Tg mice. On the other hand, hydralazine (0.5 mg/kg per day) did not improve the decrease in avoidance rate, and did not influence cerebral surface blood flow or oxidative stress in hRN/hANG-Tg mice, in spite of a similar reduction of blood pressure to that by olmesartan. Moreover, we observed that treatment with Tempol improved impaired cognitive function in hRN/hANG-Tg mice. These results suggest that continuous activation of the brain renin-angiotensin system impairs cognitive function via stimulation of the angiotensin II type 1 receptor with a decrease in cerebral surface blood flow and an increase in oxidative stress.
Volume 53(2)
Pages 356-62
Published 2009-2-1
DOI 10.1161/HYPERTENSIONAHA.108.123612
PMID 19047580
MeSH Angiotensin II Type 1 Receptor Blockers / pharmacology Angiotensinogen / genetics Angiotensinogen / metabolism* Animals Antioxidants / pharmacology Blood Pressure / physiology Brain / blood supply* Brain / metabolism* Cognition / physiology* Cyclic N-Oxides / pharmacology Imidazoles / pharmacology Male Mice Mice, Transgenic NADPH Oxidase 4 NADPH Oxidases / metabolism Oxidative Stress / physiology Receptor, Angiotensin, Type 1 / metabolism Regional Blood Flow / physiology Renin / genetics Renin / metabolism* Renin-Angiotensin System / physiology* Spin Labels Superoxides / metabolism Tetrazoles / pharmacology
IF 7.713
Times Cited 79
Mice RBRC01122 RBRC01123