Angiotensin II AT<sub>1</sub> Receptor Blockade Abolishes Brain Microvascular Inflammation and Heat Shock Protein Responses in Hypertensive Rats

Zhou, Jin; Ando, Hiromichi; Macova, Miroslava; Dou, Jingtao; Saavedra, Juan M.

doi:10.1038/sj.jcbfm.9600082

Cited by 108 publications

(119 citation statements)

References 36 publications

(67 reference statements)

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“…We did not measure the activity or levels of components of the RAAS in our rats, and it is possible that the system is upregulated in this model of renal disease. For example, it has been reported that expression of AT1R is increased in the inflamed renal parenchyma (41)(42)(43)(44)(45). Therefore, it is reasonable to speculate that higher dosages of candesartan were needed to block completely the increased numbers of AT1R in the diseased SHR kidney.…”

Section: Discussionmentioning

confidence: 99%

Long-Term, High-Dosage Candesartan Suppresses Inflammation and Injury in Chronic Kidney Disease

Chen¹,

Gong²,

Rifai

et al. 2007

Journal of the American Society of Nephrology

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Recent evidence suggests that higher-than-usual antihypertensive dosages of renin-angiotensin-aldosterone system blockers may provide additional protection from progression of chronic renal disease; however, there have been few long-term studies, and the underlying mechanisms remain uncertain. This study examined the effects of long-term (14 mo) administration of ultrahigh dosages of the angiotensin receptor blocker candesartan on the progression of renal injury in spontaneously hypertensive rats (SHR). Beginning 8 wk after birth, SHR underwent unilateral nephrectomy and were given vehicle (control), or candesartan at a standard 5 mg/kg per d (T5), high 25 mg/kg per d (T25), or ultrahigh 75 mg/kg per d dosage (T75). After 2 wk, BP was reduced in all treated groups; however, it was better controlled in the high-dosage groups (T25 and T75). Urinary protein was significantly reduced in T75 after 2 wk of treatment and was also declined in the other two treatment groups but only after 2 mo. Exogenous angiotensin II test showed that complete angiotensin receptor blockade was achieved only in the high-dosage groups. Renal inflammation and macrophage (ED-1) infiltration were significantly ameliorated in both T25 and T75 but not in T5 rats. This was associated with the changes of tubular expression of monocyte chemoattractant protein-1, RANTES (regulated upon expression normal T cell expressed and secreted), and the phosphorylated NF-B, a marker for activation. Suppression of ED-1, monocyte chemoattractant protein-1, and RANTES expression and NF-B activation were greater in T75 as compared with T25. These findings suggest that candesartan has dosage-dependent, anti-inflammatory effects that are mediated by suppression of NF-B activation and chemokine expression. Renal protection with high-dosage therapy may depend on these nonhemodynamic effects.

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Section: Discussionmentioning

confidence: 99%

Long-Term, High-Dosage Candesartan Suppresses Inflammation and Injury in Chronic Kidney Disease

Chen¹,

Gong²,

Rifai

et al. 2007

Journal of the American Society of Nephrology

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“…Brain microvessels were isolated and characterized as described previously (19). A detailed description of these techniques is also provided in SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

“…Given the high prevalence of vascular complications in DM (18), severe pathological changes in the cerebral vasculature could be detected in APP + -ob/ob mice and potentially impact on cognitive function. Thus, we isolated the microvessels from mouse brains (19) and immunostained them with anti-Aβ40 antibody. At 12 months of age, faint amyloid deposits had appeared in blood vessels in the brain of APP + mice (Fig.…”

mentioning

confidence: 99%

Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Aβ deposition in an Alzheimer mouse model with diabetes

Takeda

Sato²,

Uchio‐Yamada³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

461

403

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Recent epidemiological studies suggest that diabetes mellitus is a strong risk factor for Alzheimer disease. However, the underlying mechanisms remain largely unknown. In this study, to investigate the pathophysiological interaction between these diseases, we generated animal models that reflect the pathologic conditions of both diseases. We crossed Alzheimer transgenic mice (APP23) with two types of diabetic mice (ob/ob and NSY mice), and analyzed their metabolic and brain pathology. The onset of diabetes exacerbated Alzheimer-like cognitive dysfunction without an increase in brain amyloid-β burden in double-mutant (APP + -ob/ ob) mice. Notably, APP + -ob/ob mice showed cerebrovascular inflammation and severe amyloid angiopathy. Conversely, the cross-bred mice showed an accelerated diabetic phenotype compared with ob/ob mice, suggesting that Alzheimer amyloid pathology could aggravate diabetes. Similarly, APP + -NSY fusion mice showed more severe glucose intolerance compared with diabetic NSY mice. Furthermore, high-fat diet feeding induced severe memory deficits in APP + -NSY mice without an increase in brain amyloid-β load. Here, we created Alzheimer mouse models with early onset of cognitive dysfunction. Cerebrovascular changes and alteration in brain insulin signaling might play a pivotal role in this relationship. These findings could provide insights into this intensely debated association.β-amyloid | insulin T he incidences of Alzheimer disease (AD) and diabetes mellitus (DM) are increasing at an alarming rate and have become major public health concerns (1, 2). Interestingly, numerous epidemiological studies demonstrated that diabetic patients have a significantly higher risk of developing AD, independent of the risk for vascular dementia (2, 3). These findings raise the possibility that DM may affect fundamental AD pathogenesis. A neuropathological hallmark of AD is β-amyloid peptide (Aβ) accumulation in the brain (4). Of importance, recent data showed a clear relationship between insulin and Aβ metabolism (5-7). For example, insulin increased the extracellular Aβ level by modulating γ-secretase activity (6), or by increasing its secretion from neurons (5). Insulin-degrading enzyme, a major Aβ-degrading enzyme, might be competitively inhibited by insulin, resulting in decreased Aβ degradation (7). In addition, the brain insulin-degrading enzyme level was decreased in a hyperinsulinemic Alzheimer animal model (8). Nevertheless, unexpectedly, there is no evidence that the typical pathological hallmarks of AD, including amyloid plaque, are increased in the brain of diabetic patients (9, 10). Thus, DM could affect the pathogenesis of AD through other mechanisms than modulating Aβ metabolism. One possible mechanism is cerebrovascular alteration, a common pathological change in DM and AD. Accumulating evidence suggests the importance of Aβ-induced cerebrovascular dysfunction in AD (11). Moreover, cerebrovascular disease is a major complication of DM. Vascular inflammation or oxidative stress mediated by the ...

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“…Interestingly, there is growing evidence that SH rats and hypertensive human patients share common pathophysiological characteristics of neurogenic hypertension including vascular inflammation and cerebral microvessel alterations, which are pathognomonic for SVD. [10][11][12] Recent clinical and preclinical investigations revealed that hypertension activates a plethora of inflammatory cascades including chronic activation of microglia, 12 thereby constituting a specific prerequisite for the immunologic facet of cerebral stroke. We hence considered SH rats to be a promising animal model for studying postischemic inflammation and immunodepression closely correlated to pathophysiological conditions existing in human stroke patients.…”

Section: Introductionmentioning

confidence: 99%

Sterile Inflammation after Permanent Distal MCA Occlusion in Hypertensive Rats

Möller

Boltze²,

Pösel

et al. 2013

J Cereb Blood Flow Metab

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The pathophysiology of stroke is governed by immune reactions within and remote from the injured brain. Hypertension, a major cause and comorbidity of stroke, entails systemic vascular inflammation and may influence poststroke immune responses. This aspect is, however, underestimated in previous studies. Here we aimed to delineate the sequence of cellular inflammation after stroke in spontaneously hypertensive (SH) rats. Spontaneously hypertensive rats were subjected to permanent middle cerebral artery occlusion and killed after 1 or 4 days. Immune cells of the peripheral blood and those which have infiltrated the injured brain were identified and quantified by flow cytometry. The spatial distribution of myeloid cells and T lymphocytes, and the infarct volume were assessed by histology. We observed a concerted infiltration of immune cells into the ischemic brain of SH rats. At day 1, primarily neutrophils, monocytes, macrophages, and myeloid dendritic cells entered the brain, whereas the situation at day 4 was dominated by microglia, macrophages, lymphatic dendritic cells, and T cells. Postischemic inflammation did not cause secondary tissue damage during the subacute stage of experimental stroke in SH rats. Considering the intrinsic vascular pathology of SH rats, our study validates this strain for further translational research in poststroke inflammation.

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Angiotensin II AT₁ Receptor Blockade Abolishes Brain Microvascular Inflammation and Heat Shock Protein Responses in Hypertensive Rats

Cited by 108 publications

References 36 publications

Long-Term, High-Dosage Candesartan Suppresses Inflammation and Injury in Chronic Kidney Disease

Long-Term, High-Dosage Candesartan Suppresses Inflammation and Injury in Chronic Kidney Disease

Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Aβ deposition in an Alzheimer mouse model with diabetes

Sterile Inflammation after Permanent Distal MCA Occlusion in Hypertensive Rats

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Angiotensin II AT1 Receptor Blockade Abolishes Brain Microvascular Inflammation and Heat Shock Protein Responses in Hypertensive Rats

Cited by 108 publications

References 36 publications

Long-Term, High-Dosage Candesartan Suppresses Inflammation and Injury in Chronic Kidney Disease

Long-Term, High-Dosage Candesartan Suppresses Inflammation and Injury in Chronic Kidney Disease

Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Aβ deposition in an Alzheimer mouse model with diabetes

Sterile Inflammation after Permanent Distal MCA Occlusion in Hypertensive Rats

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Angiotensin II AT₁ Receptor Blockade Abolishes Brain Microvascular Inflammation and Heat Shock Protein Responses in Hypertensive Rats