angiotensinogen and Cognition-Disorders

Methylglyoxal (MG), one of the uremic toxins, is a highly reactive alpha-dicarbonyl compound. Recent clinical studies have demonstrated the close associations of cognitive impairment (CI) with plasma MG levels and presence of kidney dysfunction. Therefore, the present study aims to examine whether MG is a direct causative substance for CI development. Eight-week-old male Sprague-Dawley (SD) rats were divided into two groups: control (n = 9) and MG group (n = 10; 0.5% MG in drinking water), and fed a normal diet for 12 months. Cognitive function was evaluated by two behavioral tests (object exploration test and radial-arm maze test) in early (4-6 months of age) and late phase (7-12 months of age). Serum MG was significantly elevated in the MG group (495.8 ± 38.1 vs. 244.8 ± 28.2 nM; p < 0.001) at the end of study. The groups did not differ in cognitive function during the course of study. No time-course differences were found in oxidative stress markers between the two groups, while, antioxidants such as glutathione peroxidase and superoxide dismutase activities were significantly increased in the MG group compared to the control. Long-term MG administration to rats with normal kidney function did not cause CI. A counter-balanced activation of the systemic anti-oxidant system may offset the toxicity of MG in this model. Pathogenetic significance of MG for CI requires further investigation.

Topics: Administration, Oral; Angiotensinogen; Animals; Antioxidants; Cognition; Cognition Disorders; Glutathione Peroxidase; Kidney; Male; Maze Learning; Oxidative Stress; Pyruvaldehyde; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

The role of the renin-angiotensin system in cognitive impairment is unclear. This work was undertaken to test our hypothesis that renin-angiotensin system may contribute to cognitive decline and brain damage caused by chronic cerebral ischemia. C57BL/6J mice were subjected to bilateral common carotid artery stenosis with microcoil to prepare mice with chronic cerebral hypoperfusion, a model of subcortical vascular dementia. The effects of aliskiren, a direct renin inhibitor, or Tempol, a superoxide scavenger, on brain damage and working memory in these mice were examined. Chronic cerebral hypoperfusion significantly increased brain renin activity and angiotensinogen expression in C57BL/6J mice, which was attributed to the increased renin in activated astrocytes and microvessels and the increased angiotensinogen in activated astrocytes in white matter. Aliskiren pretreatment significantly inhibited brain renin activity and ameliorated brain p67(phox)-related NADPH oxidase activity, oxidative stress, glial activation, white matter lesion, and spatial working memory deficits in C57BL/6J mice with bilateral common carotid artery stenosis. To elucidate the role of oxidative stress in brain protective effects of aliskiren, we also examined the effect of Tempol in the same mice with bilateral common carotid artery stenosis. Tempol pretreatment mimicked the brain protective effects of aliskiren in this mouse model. Posttreatment of mice with aliskiren or Tempol after bilateral common carotid artery stenosis also prevented cognitive decline. In conclusion, chronic cerebral hypoperfusion induced the activation of the brain renin-angiotensin system. Aliskiren ameliorated brain damage and working memory deficits in the model of chronic cerebral ischemia through the attenuation of oxidative stress. Thus, direct renin inhibition seems to be a promising therapeutic strategy for subcortical vascular dementia.

Topics: Amides; Angiotensinogen; Animals; Antihypertensive Agents; Blood Pressure; Brain Damage, Chronic; Brain Ischemia; Cognition Disorders; Cyclic N-Oxides; Dementia, Vascular; Disease Models, Animal; Fumarates; Hypertension; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Oxidative Stress; Renin; Renin-Angiotensin System; Risk Factors; Spin Labels

To investigate the effect of polymorphisms in renin angiotensin system genes on the association between angiotensin-converting enzyme inhibitor (ACEI) exposure and global and executive cognitive function in the Health, Aging and Body Composition study.. Cohort study.. Community.. Three thousand seventy-five participants: mean age 73.6, 58% Caucasian, 52% female, 15% taking ACE-Is, 8 years of follow-up.. The outcomes were longitudinal change in Executive Clock Drawing Test-1 (CLOX1), the Digit Symbol Substitution test, and the Modified Mini-Mental State Examination. The genetic polymorphisms included angiotensin-converting enzyme insertion deletion (ACEID) in the ACE gene and the M235T and 6AG polymorphisms in the angiotensinogen (AGT) gene.. For the CLOX1 outcome, there was significant interaction between 6AG and M235T polymorphisms in the AGT gene and angiotensin-converting enzyme inhibitors (ACE-Is) in Caucasian participants (P=.01 for both polymorphisms) independent of blood pressure levels. Specifically, ACE-I exposure was protective against CLOX1 score decline in carriers of the AA genotype of the 6AG and the CC genotype of the M235T (for the ACE-I vs non-ACE-I groups, P=.01 for 6AG and P=.005 for M235T) but not the other genotypes. These associations were not significant with other cognitive tests, with ACEID, or in African Americans.. ACE-Is may provide a protective effect on executive function in Caucasians with AGT gene polymorphisms known to be associated with greater renin angiotensin system activity. If confirmed in a pharmacogenetic trial, ACE-Is may be found to have additional cognitive protection in a select group of elderly individuals.

Topics: Aged; Aging; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Body Composition; Cognition Disorders; Cohort Studies; Female; Gene Deletion; Gene Frequency; Genotype; Humans; Male; Neuropsychological Tests; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Renin-Angiotensin System; Risk Factors; White People