Continuous Activation of Renin-Angiotensin System Impairs Cognitive Function in Renin/Angiotensinogen Transgenic Mice

Inaba, Shinji; Iwai, Masaru; Furuno, Megumi; Tomono, Yumiko; Kanno, Hiroaki; Senba, Izumi; Okayama, Hideki; Mogi, Masaki; Higaki, Jitsuo; Horiuchi, Masatsugu

doi:10.1161/hypertensionaha.108.123612

Cited by 104 publications

(76 citation statements)

References 43 publications

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“…We recently showed that HFD induced changes in the expression of several genes in mice brain (12). On the other hand, recent papers reported that transgenic mice expressing human RENIN and AGT genes (hRN/hAGT-Tg) have impaired cognition, increased oxidative stress, and ischemic damage in the brain mediated by overstimulation of AT1R (32,33).…”

Section: Discussionmentioning

confidence: 99%

Side Chain-oxidized Oxysterols Regulate the Brain Renin-Angiotensin System through a Liver X Receptor-dependent Mechanism

Mateos

Ismail

Gil-Bea

et al. 2011

Journal of Biological Chemistry

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Disturbances in cholesterol metabolism have been associated with hypertension and neurodegenerative disorders. Because cholesterol metabolism in the brain is efficiently separated from plasma cholesterol by the blood-brain barrier (BBB), it is an unsolved paradox how high blood cholesterol can cause an effect in the brain. Here, we discuss the possibility that cholesterol metabolites permeable to the BBB might account for these effects. We show that 27-hydroxycholesterol (27-OH) and 24S-hydroxycholesterol (24S-OH) up-regulate the renin-angiotensin system (RAS) in the brain. Brains of mice on a cholesterol-enriched diet showed up-regulated angiotensin converting enzyme (ACE), angiotensinogen (AGT), and increased JAK/STAT activity. These effects were confirmed in in vitro studies with primary neurons and astrocytes exposed to 27-OH or 24S-OH, and were partially mediated by liver X receptors. In contrast, brain RAS activity was decreased in Cyp27a1-deficient mice, a model exhibiting reduced 27-OH production from cholesterol. Moreover, in humans, normocholesterolemic patients with elevated 27-OH levels, due to a CYP7B1 mutation, had markers of activated RAS in their cerebrospinal fluid. Our results demonstrate that side chain-oxidized oxysterols are modulators of brain RAS. Considering that levels of cholesterol and 27-OH correlate in the circulation and 27-OH can pass the BBB into the brain, we suggest that this cholesterol metabolite could be a link between high plasma cholesterol levels, hypertension, and neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Side Chain-oxidized Oxysterols Regulate the Brain Renin-Angiotensin System through a Liver X Receptor-dependent Mechanism

Mateos

Ismail

Gil-Bea

et al. 2011

Journal of Biological Chemistry

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“…Thus, it is possible that AT 1 receptor blockers reduce oxidative stress in the brain, as well as in the peripheral vasculature. It is also possible that AT 1 receptor blockers inhibit ROS production by blocking AT1 receptormediated intracellular signaling (11,48,50) and that this antioxidant action accounts for the absence of reflex-induced sympathoexcitation after treatment with AT 1 receptor blockers. We evaluated the effects of AT 1 receptor blockers, olmesartan and telmisartan, on brain oxidative stress in SHRSP (4,48).…”

Section: Sympathoinhibitory Effects Of Antihypertensive Drugs and Stamentioning

confidence: 99%

Imbalance of central nitric oxide and reactive oxygen species in the regulation of sympathetic activity and neural mechanisms of hypertension

Hirooka

Kishi

Sakai

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

109

108

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Hirooka Y, Kishi T, Sakai K, Takeshita A, Sunagawa K. Imbalance of central nitric oxide and reactive oxygen species in the regulation of sympathetic activity and neural mechanisms of hypertension. Am J Physiol Regul Integr Comp Physiol 300: R818-R826, 2011. First published February 2, 2011 doi:10.1152/ajpregu.00426.2010 and reactive oxygen species (ROS) play important roles in blood pressure regulation via the modulation of the autonomic nervous system, particularly in the central nervous system (CNS). In general, accumulating evidence suggests that NO inhibits, but ROS activates, the sympathetic nervous system. NO and ROS, however, interact with each other. Our consecutive studies and those of others strongly indicate that an imbalance between NO bioavailability and ROS generation in the CNS, including the brain stem, activates the sympathetic nervous system, and this mechanism is involved in the pathogenesis of neurogenic aspects of hypertension. In this review, we focus on the role of NO and ROS in the regulation of the sympathetic nervous system within the brain stem and subsequent cardiovascular control. Multiple mechanisms are proposed, including modulation of neurotransmitter release, inhibition of receptors, and alterations of intracellular signaling pathways. Together, the evidence indicates that an imbalance of NO and ROS in the CNS plays a pivotal role in the pathogenesis of hypertension. blood pressure; sympathetic nervous system; central nervous system; nitric oxide; oxidative stress ACTIVATION OF THE SYMPATHETIC nervous system is critically involved in the pathogenesis of hypertension, from initial occurrence to the development of target organ damage, such as heart failure, stroke, and renal failure (35,36). The importance of the effects of the renin-angiotensin system on the sympathetic nervous system in the pathogenesis of hypertension is recently highlighted (30,31). This is not surprising because both the autonomic nervous system and hormonal factors are the major regulators of blood pressure; therefore, abnormalities of either system are likely to be involved in the pathogenesis of essential hypertension (30,31,37). Esler (30) reported that the sympathetic nervous system is activated in ϳ50% of patients with hypertension, particularly in patients with essential hypertension. Central sympathetic outflow is determined by several important nuclei and their circuits in the central nervous system (CNS) (9, 81). These pathways involve many neurotransmitters and neuromodulators (16,25,38,99). In particular, the brain stem circuitry is now considered crucial for the pathogenesis of hypertension, including both excitatory and inhibitory inputs from the supramedullary nuclei and the baroreceptors (16,25,38,100,115). In this review, we focus on the role of nitric oxide (NO) and reactive oxygen species (ROS) in the brain stem as factors constituting the neural mechanisms of hypertension. Because of the close relationship between NO and ROS, we discuss the individual roles of NO and ROS in the brain stem i...

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“…6 PREVENTION OF METABOLIC SYNDROME-INDUCED DEMENTIA Continuous activation of the brain RAS impairs cognitive function through stimulation of the AT 1 receptor. 23 The ARB candesartan ameliorates impaired cognitive function in mice with type 2 diabetes (KKAy), at least partly, because of increased expression of MMS2 and an improvement in glucose intolerance. 24 Interestingly, another ARB, olmesartan, is therapeutically effective at preventing the impairment of cognition in mice fed a high-fat and high-salt diet.…”

Section: Enhancement Of Neural Differentiationmentioning

confidence: 99%

Effects of angiotensin II receptor blockers on dementia

Mogi

Horiuchi

2009

Hypertens Res

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The renin-angiotensin system (RAS) is involved in pathological mechanisms of target organ damage as well as the induction of hypertension; therefore, blockade of the RAS has been expected to prevent cardiovascular and cerebrovascular diseases beyond its antihypertensive effects. In spite of the well-characterized role of angiotensin (Ang) II receptor blockers (ARBs) in preventing the onset and recurrence of stroke, the clinical evidence for an effect of ARBs on dementia has not been definitive. However, preliminary experiments raise the possibility that treatment using ARBs may prevent ischemic brain damage and cognitive impairment. Moreover, recent reports have shown that some ARBs prevent amyloid b deposition in the brain and attenuate cognitive impairment in Alzheimer disease models. Furthermore, recent cohort studies indicate that lower incidence of Alzheimer disease is observed in elderly individuals treated with ARBs. These results indicate a beneficial role for ARBs in cognitive impairment associated with vascular disease, Alzheimer disease, metabolic syndrome and other neurodegenerative diseases. Here, we review the effects of ARBs on the brain with a focus on dementia and future therapeutic approaches for elderly people suffering from disabilities. Hypertension Research (2009) 32, 738-740; doi:10.1038/hr.2009 Keywords: dementia; neuroinflammation; neuroprotective; renin-angiotensin system; stroke INTRODUCTION Dementia is a common but serious health problem. An estimated 33 million elderly persons around the world suffer from dementia, and this number is expected to reach 81.1 million by 2040. 1 Dementia impairs quality of life and is associated with a profound disease burden, morbidity and mortality, not only in patients but also in caregivers. 2,3 Therefore, prevention of dementia is a critical need for advanced countries to address. Life style-related disorders, such as hypertension, diabetes mellitus and obesity have been reported to be related to dementia. For example, large prospective cohort studies indicate that midlife hypertension increases the risk of dementia, 4 suggesting that the blood pressure-lowering effects of antihypertensive drugs may reduce the incidence of dementia. Moreover, recent clinical studies and basic research have suggested several ways in which antihypertensive drugs can prevent target organ damage independently of their antihypertensive effect. In particular, the tissue reninangiotensin system (RAS) (the so-called local RAS) is involved not only in the vasculature but also in the brain. Accumulating evidence from large clinical trials suggests that blockade of the RAS by angiotensin (Ang) II type 1 (AT 1 ) receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors is more effective at inhibiting target organ (such as heart and kidney) damage than other hypertensive agents. 5 Here, we overview the accumulating evidence and suggest possible mechanisms by which ARBs prevent brain damage and dementia.

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Continuous Activation of Renin-Angiotensin System Impairs Cognitive Function in Renin/Angiotensinogen Transgenic Mice

Cited by 104 publications

References 43 publications

Side Chain-oxidized Oxysterols Regulate the Brain Renin-Angiotensin System through a Liver X Receptor-dependent Mechanism

Side Chain-oxidized Oxysterols Regulate the Brain Renin-Angiotensin System through a Liver X Receptor-dependent Mechanism

Imbalance of central nitric oxide and reactive oxygen species in the regulation of sympathetic activity and neural mechanisms of hypertension

Effects of angiotensin II receptor blockers on dementia

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