Although it is feared that diabetes-induced cognitive decline will become a major clinical problem worldwide in the future, the detailed pathological mechanism is not well known. Because patients ...with diabetes have various complications of vascular disease, with not only macrovascular but also microvascular disorders, vascular disorders in the brain are considered to be one of the mechanisms in diabetes-induced cognitive impairment. Indeed, disruption of the blood-brain barrier (BBB) has been observed in some diabetic patients and experimental diabetes models. Moreover, white matter lesions, part of the evidence of BBB dysfunction, are reported to be observed more frequently in patients with diabetes. Animal studies demonstrate that diabetes enhances BBB permeability through a decrease in the level of tight junction proteins and an increase in matrix metalloproteinase activity. However, there are several reports indicating that BBB disruption does not occur with diabetes. Therefore, the association of BBB breakdown with diabetes-induced cognitive impairment is not conclusive. Recently, neuronal diseases involving dementia have been induced experimentally through dysfunction of neurovascular coupling, which involves blood vessels, astrocytes and neutrons. Diabetes-induced cognitive decline may be induced via disruption of neurovascular coupling, with not only vascular disorder but also impairment of astrocytic trafficking. Here, the relation between vascular disorder and cognitive impairment in diabetes is discussed. (Circ J 2011; 75: 1042-1048)
Inhibition of the renin-angiotensin system (RAS) has been shown to alleviate muscle atrophy both under pathological conditions and during physiological aging. We recently reported that the deletion ...of angiotensin converting enzyme 2 (ACE2), which converts Angiotensin II to Angiotensin-(1-7) in mice, leads to the early manifestation of aging-associated muscle weakness along with the increased expression of p16
, a senescence-associated gene, and increased central nuclei in the tibialis anterior (TA) muscle in middle age. As ACE2 is multifunctional and functions beyond its role in the RAS, we investigated whether activation of the RAS primarily contributes to muscle weakness in ACE2 knockout (KO) mice by comparing these mice to Tsukuba hypertensive (TH) mice that overproduce human angiotensin II. The grip strength of young (6 months) and middle-aged (15 months) TH mice was consistently lower than that of wild-type mice at the same ages. Middle-aged TH mice were continuously lean with extremely reduced adiposity. Central nuclei in the gastrocnemius (GM) muscle were increased in ACE2KO mice, while no apparent morphological change was observed in the GM muscles of TH mice. Increased expression of p16
along with alterations in the expression of several sarcopenia-associated genes were observed in the GM muscles of ACE2KO mice but not TH mice. These findings suggest that chronic overactivation of the RAS does not primarily contribute to the early aging phenotypes of skeletal muscle in ACE2KO mice.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Recent clinical studies have demonstrated that angiotensin II type 1 (AT1) receptor blockers (ARBs) reduce the onset of stroke, stroke severity and the incidence and progression of Alzheimer's ...disease and dementia. We can expect that ARBs exert these effects by both AT1 receptor blockade and angiotensin II type 2 (AT2) receptor stimulation. Moreover, recent experimental results support the notion that AT2 receptor stimulation with AT1 receptor blockade could contribute to protection against ischaemic brain damage at least partly due to an increase in cerebral blood flow and decrease in oxidative stress, and prevent cognitive decline. Cellular therapy has been focused on as a new therapeutic approach to restore injured neurons. In this context, it has been reported that AT2 receptor stimulation enhances neurite outgrowth and decreases neural damage, thereby enhancing neurogenesis. Moreover, additional beneficial effects of ARBs with an AT1 receptor blocking action with a partial peroxisome proliferator‐activated receptor (PPAR)‐γ agonistic effect have been reported, and interaction of AT2 receptor activation and PPAR‐γ might be involved in these ARBs' effects. This article reviews the effects of regulation of activation of angiotensin II receptor subtypes on ischaemic brain damage and cognitive function, focusing on the effects of AT2 receptor stimulation.
LINKED ARTICLES This article is one of a set of reviews submitted to BJP in connection with talks given at the September 2010 meeting of the International Society of Hypertension in Vancouver, Canada. To view the other articles in this collection visit http://dx.doi.org/10.1111/j.1476‐5381.2011.01235.x, http://dx.doi.org/10.1111/j.1476‐5381.2011.01260.x and http://dx.doi.org/10.1111/j.1476‐5381.2011.01366.x
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The RAS (renin-angiotensin system) plays a role not only in the cardiovascular system, including blood pressure regulation, but also in the central nervous system. AngII (angiotensin II) binds two ...major receptors: the AT(1) receptor (AngII type 1 receptor) and AT(2) receptor (AngII type 2 receptor). It has been recognized that AT(2) receptor activation not only opposes AT(1) receptor actions, but also has unique effects beyond inhibitory cross-talk with AT(1) receptor signalling. Novel pathways beyond the classical actions of RAS, the ACE (angiotensin-converting enzyme)/AngII/AT(1) receptor axis, have been highlighted: the ACE2/Ang-(1-7) angiotensin-(1-7)/Mas receptor axis as a new opposing axis against the ACE/AngII/AT(1) receptor axis, novel AngII-receptor-interacting proteins and various AngII-receptor-activation mechanisms including dimer formation. ATRAP (AT(1)-receptor-associated protein) and ATIP (AT(2)-receptor-interacting protein) are well-characterized AngII-receptor-associated proteins. These proteins could regulate the functions of AngII receptors and thereby influence various pathophysiological states. Moreover, the possible cross-talk between PPAR (peroxisome-proliferator-activated receptor)-γ and AngII receptor subtypes is an intriguing issue to be addressed in order to understand the roles of RAS in the metabolic syndrome, and interestingly some ARBs (AT(1)-receptor blockers) have been reported to have an AT(1)-receptor-blocking action with a partial PPAR-γ agonistic effect. These emerging concepts concerning the regulation of AngII receptors are discussed in the present review.
Patients with chronic kidney disease (CKD) are well known to have a higher prevalence of cardiovascular disease from epidemiological studies. Recently, CKD has also been shown to be related to ...neurological disorders, not only ischemic brain injury but also cognitive impairment. This cerebrorenal connection is considered to involve small vessel disease in both the kidney and brain, based on their hemodynamic similarities. Clinical studies suggest that markers for CKD such as estimated glomerular filtration rate (eGFR), proteinuria, and albuminuria may be helpful to predict brain small vessel disease, white matter lesions (WMLs), silent brain ischemia (SBI), and microhemorrhages. Recently, changes in the vascular system of the brain have been shown to contribute to the onset and progression of cognitive impairment, not only vascular dementia but also Alzheimer's disease. Patients with CKD are also reported to have higher risk of impaired cognitive function in the future compared with non-CKD subjects. These results indicate that CKD markers may be helpful to predict the future risk of neuronal disease.
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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 beta 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.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Here, we briefly review the role of the renin–angiotensin system (RAS) in cognitive impairment and neurodegenerative disease, mainly discussing our experimental studies on the angiotensin II type 2 ...(AT2) receptor. Ischemic brain damage is enhanced in mice with overexpression of angiotensin II, with reduced cerebral blood flow in the penumbra and an increase in oxidative stress in the ischemic area. Angiotensin II binds two types of receptors, type 1 (AT1) and type 2 (AT2). Our previous experiments showed that AT1 receptor signaling has a harmful effect, and AT2 receptor signaling has a protective effect on the brain after stroke. AT2 receptor signaling in bone marrow stromal cells or hematopoietic cells was shown to prevent ischemic brain damage after middle cerebral artery occlusion. In contrast, AT2 receptor signaling also affects cognitive function. We showed that direct stimulation of the AT2 receptor by a newly generated direct AT2 receptor agonist, Compound 21 (C21), enhanced cognitive function in wild‐type (C57BL6) mice and an Alzheimer's disease mouse model with intracerebroventricular injection of amyloid β (1–40). Finally, we carried out clinical research by investigating the levels of RAS components in patients with neurodegenerative diseases. We observed a reduction of angiotensin II and angiotensin converting enzyme (ACE) 2 levels, and an increase in ACE level in cerebrospinal fluid from patients with multiple sclerosis. These results suggest that RAS is also involved in neurodegenerative disease. Therefore, regulation of RAS might be a new therapeutic target to protect neurons from neural diseases. Geriatr Gerontol Int 2012; ••: ••–••.
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The angiotensin type 2 receptor (AT2R) and the receptor MAS are receptors of the protective arm of the renin-angiotensin system. They mediate strikingly similar actions. Moreover, in various studies, ...AT2R antagonists blocked the effects of MAS agonists and vice versa. Such cross-inhibition may indicate heterodimerization of these receptors. Therefore, this study investigated the molecular and functional interplay between MAS and the AT2R. Molecular interactions were assessed by fluorescence resonance energy transfer and by cross correlation spectroscopy in human embryonic kidney-293 cells transfected with vectors encoding fluorophore-tagged MAS or AT2R. Functional interaction of AT2R and MAS was studied in astrocytes with CX3C chemokine receptor-1 messenger RNA expression as readout. Coexpression of fluorophore-tagged AT2R and MAS resulted in a fluorescence resonance energy transfer efficiency of 10.8 ± 0.8%, indicating that AT2R and MAS are capable to form heterodimers. Heterodimerization was verified by competition experiments using untagged AT2R and MAS. Specificity of dimerization of AT2R and MAS was supported by lack of dimerization with the transient receptor potential cation channel, subfamily C-member 6. Dimerization of the AT2R was abolished when it was mutated at cysteine residue 35. AT2R and MAS stimulation with the respective agonists, Compound 21 or angiotensin-(1-7), significantly induced CX3C chemokine receptor-1 messenger RNA expression. Effects of each agonist were blocked by an AT2R antagonist (PD123319) and also by a MAS antagonist (A-779). Knockout of a single of these receptors made astrocytes unresponsive for both agonists. Our results suggest that MAS and the AT2R form heterodimers and that-at least in astrocytes-both receptors functionally depend on each other.
There is a growing interest in identifying natural food ingredients that may serve to prevent dementia such as that due to Alzheimer disease (AD). Peptides derived from food proteins have been ...demonstrated to have various physiological activities such as a hypotensive action. Recent findings have indicated possible associations of hypertension with AD progression, and suggest that angiotensin converting enzyme (ACE) inhibitors with potential to pass through the blood brain barrier (BBB) may reduce the risk of AD. In this study, we investigated the effect of milk peptide (CH-3) on cognitive function in AD model mice. CH-3 contains a tripeptide (methionine-lysine-proline, MKP) that has been found to have a strong ACE inhibitory effect and the potential to pass through the BBB. Adult male ddY mice were used in this study, and an animal model of AD was induced by intracerebroventricular (ICV) injection of Aβ1-42. CH-3 (250 mg/kg/day) or MKP (0.5 mg/kg/day) was orally administered every day starting 2 days before ICV injection. At 3 weeks after ICV injection, cognitive function was evaluated by the Morris water maze test. Brain samples were obtained after behavioral testing, and expression of inflammatory cytokines and NADPH oxidase subunits was measured by real-time quantitative RT-PCR. ICV injection of Aβ1-42 significantly impaired cognitive function compared with that in PBS-injected mice. Daily administration of CH-3 markedly attenuated this Aβ1-42-induced cognitive decline. Aβ1-42 injection significantly enhanced the expression of tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS) and p22phox in the mouse hippocampus compared with PBS injection, and showed a tendency to increase the expression of monocyte chemoattractant protein-1 (MCP-1), p47phox and gp91phox, whereas CH-3 treatment markedly reduced Aβ1-42-induced TNF-α, MCP-1, iNOS, p47phox and gp91phox expression. Finally, administration of MKP also attenuated Aβ1-42-induced cognitive impairment with an increase in cerebral blood flow. The present study demonstrated that repeated oral administration of CH-3 to AD model mice not only improved cognitive function but also suppressed the expression of inflammatory cytokines and production of oxidative stress, and suggests its therapeutic potential for preventing cognitive impairment in AD.
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