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1.
Am J Physiol Regul Integr Comp Physiol ; 312(6): R973-R981, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28490451

RESUMO

Direct intracerebroventricular injection of angiotensin II (ANG II) causes increases in blood pressure and salt and water intake, presumably mimicking an effect mediated by an endogenous mechanism. The subfornical organ (SFO) is a potential source of cerebrospinal fluid (CSF), ANG I, and ANG II, and thus we hypothesized that the SFO has a secretory function. Endogenous levels of angiotensinogen (AGT) and renin are very low in the brain. We therefore examined the immunohistochemical localization of angiotensin peptides and AGT in the SFO, and AGT in the CSF in two transgenic models that overexpress either human AGT (A+ mice), or both human AGT (hAGT) and human renin (SRA mice) in the brain. Measurements were made at baseline and following volumetric depletion of CSF. Ultrastructural analysis with immunoelectron microscopy revealed that superficially located ANG I/ANG II and AGT immunoreactive cells in the SFO were vacuolated and opened directly into the ventricle. Withdrawal of CSF produced an increase in AGT in the CSF that was accompanied by a large decline in AGT immunoreactivity within SFO cells. Our data provide support for the hypothesis that the SFO is a secretory organ that releases AGT and possibly ANG I/ANG II into the ventricle at least under conditions when genes that control the renin-angiotensin system are overexpressed in mice.


Assuntos
Angiotensina II/metabolismo , Angiotensina I/metabolismo , Angiotensinogênio/metabolismo , Ventrículos Cerebrais/metabolismo , Sistema Renina-Angiotensina , Órgão Subfornical/metabolismo , Angiotensina I/líquido cefalorraquidiano , Angiotensina II/líquido cefalorraquidiano , Angiotensinogênio/líquido cefalorraquidiano , Angiotensinogênio/genética , Animais , Ventrículos Cerebrais/ultraestrutura , Genótipo , Humanos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , Renina/genética , Renina/metabolismo , Sistema Renina-Angiotensina/genética , Órgão Subfornical/ultraestrutura , Fatores de Tempo , Regulação para Cima
2.
JCI Insight ; 2(8)2017 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-28422749

RESUMO

Nonalcoholic fatty liver disease (NAFLD), characterized by an excess accumulation of hepatic triglycerides, is a growing health epidemic. While ER stress in the liver has been implicated in the development of NAFLD, the role of brain ER stress - which is emerging as a key contributor to a number of chronic diseases including obesity - in NAFLD remains unclear. These studies reveal that chemical induction of ER stress in the brain caused hepatomegaly and hepatic steatosis in mice. Conversely, pharmacological reductions in brain ER stress in diet-induced obese mice rescued NAFLD independent of body weight, food intake, and adiposity. Evaluation of brain regions involved revealed robust activation of ER stress biomarkers and ER ultrastructural abnormalities in the circumventricular subfornical organ (SFO), a nucleus situated outside of the blood-brain-barrier, in response to high-fat diet. Targeted reductions in SFO-ER stress in obese mice via SFO-specific supplementation of the ER chaperone 78-kDa glucose-regulated protein ameliorated hepatomegaly and hepatic steatosis without altering body weight, food intake, adiposity, or obesity-induced hypertension. Overall, these findings indicate a novel role for brain ER stress, notably within the SFO, in the pathogenesis of NAFLD.

3.
Hypertension ; 68(6): 1385-1392, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27754863

RESUMO

The renin-angiotensin system (RAS) in the brain is a critical determinant of blood pressure, but the mechanisms regulating RAS activity in the brain remain unclear. Expression of brain renin (renin-b) occurs from an alternative promoter-first exon. The predicted translation product is a nonsecreted enzymatically active renin whose function is unknown. We generated a unique mouse model by selectively ablating the brain-specific isoform of renin (renin-b) while preserving the expression and function of the classical isoform expressed in the kidney (renin-a). Preservation of renal renin was confirmed by measurements of renin gene expression and immunohistochemistry. Surprisingly, renin-b-deficient mice exhibited hypertension, increased sympathetic nerve activity to the kidney and heart, and impaired baroreflex sensitivity. Whereas these mice displayed decreased circulating RAS activity, there was a paradoxical increase in brain RAS activity. Physiologically, renin-b-deficient mice exhibited an exaggerated depressor response to intracerebroventricular administration of losartan, captopril, or aliskiren. At the molecular level, renin-b-deficient mice exhibited increased expression of angiotensin-II type 1 receptor in the paraventricular nucleus, which correlated with an increased renal sympathetic nerve response to leptin, which was dependent on angiotensin-II type 1 receptor activity. Interestingly, despite an ablation of renin-b expression, expression of renin-a was significantly increased in rostral ventrolateral medulla. These data support a new paradigm for the genetic control of RAS activity in the brain by a coordinated regulation of the renin isoforms, with expression of renin-b tonically inhibiting expression of renin-a under baseline conditions. Impairment of this control mechanism causes neurogenic hypertension.


Assuntos
Deleção de Genes , Hipertensão/fisiopatologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Sistema Renina-Angiotensina/genética , Renina/genética , Análise de Variância , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Hipertensão/tratamento farmacológico , Hipertensão/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Isoformas de Proteínas/metabolismo , Distribuição Aleatória , Sistema Renina-Angiotensina/efeitos dos fármacos , Sensibilidade e Especificidade
4.
Endocrinology ; 157(11): 4266-4275, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27575030

RESUMO

Peroxisome proliferator activated receptor (PPARγ) is a nuclear receptor transcription factor that regulates adipogenesis and energy homeostasis. Recent studies suggest PPARγ may mediate some of its metabolic effects through actions in the brain. We used a Cre-recombinase-dependent (using NestinCre) conditionally activatable transgene expressing either wild-type (WT) or dominant-negative (P467L) PPARγ to examine mechanisms by which PPARγ in the nervous system controls energy balance. Inducible expression of PPARγ was evident throughout the brain. Expression of 2 PPARγ target genes, aP2 and CD36, was induced by WT but not P467L PPARγ in the brain. Surprisingly, NesCre/PPARγ-WT mice exhibited severe microcephaly and brain malformation, suggesting that PPARγ can modulate brain development. On the contrary, NesCre/PPARγ-P467L mice exhibited blunted weight gain to high-fat diet, which correlated with a decrease in lean mass and tissue masses, accompanied by elevated plasma GH, and depressed plasma IGF-1, indicative of GH resistance. There was no expression of the transgene in the pancreas but both fasting plasma glucose, and fed and fasted plasma insulin levels were markedly decreased. NesCre/PPARγ-P467L mice fed either control diet or high-fat diet displayed impaired glucose tolerance yet exhibited increased sensitivity to exogenous insulin and increased insulin receptor signaling in white adipose tissue, liver, and skeletal muscle. These observations support the concept that alterations in PPARγ-driven mechanisms in the nervous system play a role in the regulation of growth and glucose metabolic homeostasis.


Assuntos
Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , PPAR gama/metabolismo , Adipogenia/genética , Adipogenia/fisiologia , Animais , Composição Corporal/genética , Composição Corporal/fisiologia , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/genética , Metabolismo Energético/fisiologia , Jejum/sangue , Glucose/metabolismo , Teste de Tolerância a Glucose , Humanos , Insulina/metabolismo , Resistência à Insulina/genética , Resistência à Insulina/fisiologia , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Mutação , PPAR gama/genética , Receptor de Insulina/genética , Receptor de Insulina/metabolismo
5.
Cell Metab ; 23(2): 335-43, 2016 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-26724858

RESUMO

The liver is an important integrator of nutrient metabolism, yet no liver-derived factors regulating nutrient preference or carbohydrate appetite have been identified. Here we show that the liver regulates carbohydrate intake through production of the hepatokine fibroblast growth factor 21 (FGF21), which markedly suppresses consumption of simple sugars, but not complex carbohydrates, proteins, or lipids. Genetic loss of FGF21 in mice increases sucrose consumption, whereas acute administration or overexpression of FGF21 suppresses the intake of both sugar and non-caloric sweeteners. FGF21 does not affect chorda tympani nerve responses to sweet tastants, instead reducing sweet-seeking behavior and meal size via neurons in the hypothalamus. This liver-to-brain hormonal axis likely represents a negative feedback loop as hepatic FGF21 production is elevated by sucrose ingestion. We conclude that the liver functions to regulate macronutrient-specific intake by producing an endocrine satiety signal that acts centrally to suppress the intake of "sweets."


Assuntos
Sistema Endócrino/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Preferências Alimentares/efeitos dos fármacos , Fígado/metabolismo , Sacarose/farmacologia , Paladar/efeitos dos fármacos , Animais , Sistema Endócrino/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Camundongos Knockout , Proteínas Nucleares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo
6.
Basal Ganglia ; 5(2-3): 51-55, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-26251824

RESUMO

INTRODUCTION: The involvement of dopaminergic neurons in the ventral tegmental area (VTA) in Parkinson's disease (PD) has not been universally recognized by neuroscientists and neurologists. Here, we conduct a review of previous research documenting dopaminergic neuronal loss in both the substantia nigra pars compacta (SNpc) and VTA and add three new post-mortem PD cases to the literature. METHODS: PD and control brains were sectioned, stained for tyrosine hydroxylase, and cells in the SNpc and VTA were counted. RESULTS: Based on the review, we report two main results: 1) the VTA does degenerate in PD, and 2) the VTA degenerates less than the SNpc. CONCLUSION: Inconsistent clinical information about these cases limits our ability to interpret how the VTA contributes to PD symptoms. However, our data in combination with prior PD neuropathological cases in the literature unequivocally establish that the VTA is involved in PD, and could be relevant for future investigation of non-motor symptoms in PD.

7.
Hypertension ; 65(6): 1341-8, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25895586

RESUMO

Endoplasmic reticulum stress has become an important mechanism in hypertension. We examined the role of endoplasmic reticulum stress in mediating the increased saline-intake and hypertensive effects in response to deoxycorticosterone acetate (DOCA)-salt. Intracerebroventricular delivery of the endoplasmic reticulum stress-reducing chemical chaperone tauroursodeoxycholic acid did not affect the magnitude of hypertension, but markedly decreased saline-intake in response to DOCA-salt. Increased saline-intake returned after tauroursodeoxycholic acid was terminated. Decreased saline-intake was also observed after intracerebroventricular infusion of 4-phenylbutyrate, another chemical chaperone. Immunoreactivity to CCAAT homologous binding protein, a marker of irremediable endoplasmic reticulum stress, was increased in the subfornical organ and supraoptic nucleus of DOCA-salt mice, but the signal was absent in control and CCAAT homologous binding protein-deficient mice. Electron microscopy revealed abnormalities in endoplasmic reticulum structure (decrease in membrane length, swollen membranes, and decreased ribosome numbers) in the subfornical organ consistent with endoplasmic reticulum stress. Subfornical organ-targeted adenoviral delivery of GRP78, a resident endoplasmic reticulum chaperone, decreased DOCA-salt-induced saline-intake. The increase in saline-intake in response to DOCA-salt was blunted in CCAAT homologous binding protein-deficient mice, but these mice exhibited a normal hypertensive response. We conclude that (1) brain endoplasmic reticulum stress mediates the saline-intake, but not blood pressure response to DOCA-salt, (2) DOCA-salt causes endoplasmic reticulum stress in the subfornical organ, which when attenuated by GRP78 blunts saline-intake, and (3) CCAAT homologous binding protein may play a functional role in DOCA-salt-induced saline-intake. The results suggest a mechanistic distinction between the importance of endoplasmic reticulum stress in mediating effects of DOCA-salt on saline-intake and blood pressure.


Assuntos
Encéfalo/metabolismo , Acetato de Desoxicorticosterona/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hipertensão/fisiopatologia , Cloreto de Sódio/farmacologia , Análise de Variância , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/fisiologia , Infusões Intraventriculares , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Valores de Referência , Sensibilidade e Especificidade , Cloreto de Sódio/metabolismo , Estatísticas não Paramétricas , Órgão Subfornical/efeitos dos fármacos , Órgão Subfornical/fisiopatologia
8.
Hypertension ; 64(3): 590-6, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24914194

RESUMO

S-P467L mice expressing dominant negative peroxisome proliferator-activated receptor-γ selectively in vascular smooth muscle exhibit impaired vasodilation, augmented vasoconstriction, hypertension, and tachycardia. We hypothesized that tachycardia in S-P467L mice is a result of baroreflex dysfunction. S-P467L mice displayed increased sympathetic traffic to the heart and decreased baroreflex gain and effectiveness. Carotid arteries exhibited inward remodeling but no changes in distensibility or stress/strain. Aortic depressor nerve activity in response to increased arterial pressure was blunted in S-P467L mice. However, the arterial pressure and heart rate responses to aortic depressor nerve stimulation were unaltered in S-P467L mice, suggesting that the central and efferent limbs of the baroreflex arc remain intact. There was no transgene expression in nodose ganglion and no change in expression of the acid-sensing ion channel-2 or -3 in nodose ganglion. There was a trend toward decreased expression of transient receptor potential vanilloid-1 receptor mRNA in nodose ganglion, but no difference in the immunochemical staining of transient receptor potential vanilloid-1 receptor in the termination area of the left aortic depressor nerve in S-P467L mice. Although there was no difference in the maximal calcium response to capsaicin in cultured nodose neurons from S-P467L mice, there was decreased desensitization of transient receptor potential vanilloid-1 receptor channels. In conclusion, S-P467L mice exhibit baroreflex dysfunction because of a defect in the afferent limb of the baroreflex arc caused by impaired vascular function, altered vascular structure, or compromised neurovascular coupling. These findings implicate vascular smooth muscle peroxisome proliferator activated receptor-γ as a critical determinant of neurovascular signaling.


Assuntos
Doenças do Sistema Nervoso Autônomo/fisiopatologia , Barorreflexo/fisiologia , Músculo Liso Vascular/fisiopatologia , PPAR gama/fisiologia , Taquicardia/fisiopatologia , Animais , Sistema Nervoso Autônomo/fisiopatologia , Pressão Sanguínea/fisiologia , Cálcio/metabolismo , Capsaicina/farmacologia , Células Cultivadas , Modelos Animais de Doenças , Frequência Cardíaca/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Gânglio Nodoso/efeitos dos fármacos , Gânglio Nodoso/fisiologia , PPAR gama/deficiência , PPAR gama/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
9.
Am J Physiol Regul Integr Comp Physiol ; 307(4): R376-86, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-24965793

RESUMO

Increased activity of the renin-angiotensin system within the brain elevates fluid intake, blood pressure, and resting metabolic rate. Renin and angiotensinogen are coexpressed within the same cells of the subfornical organ, and the production and action of ANG II through the ANG II type 1 receptor in the subfornical organ (SFO) are necessary for fluid intake due to increased activity of the brain renin-angiotensin system. We generated an inducible model of ANG II production by breeding transgenic mice expressing human renin in neurons controlled by the synapsin promoter with transgenic mice containing a Cre-recombinase-inducible human angiotensinogen construct. Adenoviral delivery of Cre-recombinase causes SFO-selective induction of human angiotensinogen expression. Selective production of ANG II in the SFO results in increased water intake but did not change blood pressure or resting metabolic rate. The increase in water intake was ANG II type 1 receptor-dependent. When given a choice between water and 0.15 M NaCl, these mice increased total fluid and sodium, but not water, because of an increased preference for NaCl. When provided a choice between water and 0.3 M NaCl, the mice exhibited increased fluid, water, and sodium intake, but no change in preference for NaCl. The increase in fluid intake was blocked by an inhibitor of PKC, but not ERK, and was correlated with increased phosphorylated cyclic AMP response element binding protein in the subfornical organ. Thus, increased production and action of ANG II specifically in the subfornical organ are sufficient on their own to mediate an increase in drinking through PKC.


Assuntos
Angiotensinogênio/metabolismo , Ingestão de Líquidos , Sistema Renina-Angiotensina , Renina/metabolismo , Órgão Subfornical/enzimologia , Angiotensinogênio/genética , Animais , Comportamento Animal , Pressão Sanguínea , Proteína de Ligação a CREB/metabolismo , Ingestão de Líquidos/efeitos dos fármacos , Comportamento de Ingestão de Líquido , Metabolismo Energético , Feminino , Humanos , Integrases/genética , Proteínas Luminescentes/biossíntese , Proteínas Luminescentes/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fosforilação , Regiões Promotoras Genéticas , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Renina/genética , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/genética , Transdução de Sinais , Cloreto de Sódio/administração & dosagem , Órgão Subfornical/efeitos dos fármacos , Sinapsinas/genética , Fatores de Tempo
10.
Hypertension ; 64(1): 141-8, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24777977

RESUMO

Angiotensin-II production in the subfornical organ acting through angiotensin-II type-1 receptors is necessary for polydipsia, resulting from elevated renin-angiotensin system activity. Protein kinase C and mitogen-activated protein kinase pathways have been shown to mediate effects of angiotensin-II in the brain. We investigated mechanisms that mediate brain angiotensin-II-induced polydipsia. We used double-transgenic sRA mice, consisting of human renin controlled by the neuron-specific synapsin promoter crossed with human angiotensinogen controlled by its endogenous promoter, which results in brain-specific overexpression of angiotensin-II, particularly in the subfornical organ. We also used the deoxycorticosterone acetate-salt model of hypertension, which exhibits polydipsia. Inhibition of protein kinase C, but not extracellular signal-regulated kinases, protein kinase A, or vasopressin V1A and V2 receptors, corrected the elevated water intake of sRA mice. Using an isoform selective inhibitor and an adenovirus expressing dominant negative protein kinase C-α revealed that protein kinase C-α in the subfornical organ was necessary to mediate elevated fluid and sodium intake in sRA mice. Inhibition of protein kinase C activity also attenuated polydipsia in the deoxycorticosterone acetate-salt model. We provide evidence that inducing protein kinase C activity centrally is sufficient to induce water intake in water-replete wild-type mice, and that cell surface localization of protein kinase C-α can be induced in cultured cells from the subfornical organ. These experimental findings demonstrate a role for central protein kinase C activity in fluid balance, and further mechanistically demonstrate the importance of protein kinase C-α signaling in the subfornical organ in fluid intake stimulated by angiotensin-II in the brain.


Assuntos
Encéfalo/metabolismo , Ingestão de Líquidos/fisiologia , Proteína Quinase C-alfa/metabolismo , Sistema Renina-Angiotensina/fisiologia , Órgão Subfornical/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Feminino , Hipertensão/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Proteína Quinase C-alfa/antagonistas & inibidores , Sistema Renina-Angiotensina/efeitos dos fármacos , Órgão Subfornical/efeitos dos fármacos
11.
Cerebrovasc Dis ; 35(3): 262-7, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23548816

RESUMO

BACKGROUND: It has been described that lacunar infarct is characterized by its smallish size (15-20 mm) in the axial plane. However, the size of the basal ganglia artery responsible for this type of infarct is uncertain. Detection of small arterial occlusion is not possible with current angiography, hindering correlation of arterial occlusion with subcortical infarct size. Recently, investigators have published microangiographic templates of arteries supplying the basal ganglia. These templates display first-order (proximal) to third-order (distal) branching of these arteries and can help with estimating the likely site of arterial disease in subcortical infarcts. We correlated the dimensions of subcortical infarcts with the order of arterial branching described in a microangiographic template. Such data may provide further clues about the type of arteries associated with subcortical infarcts and assist in refining the concept of lacunar infarction. METHOD: Patients with subcortical infarcts on MR imaging (MRI) admitted to our institution between 2009 and 2011 were included in the study. Infarcts were manually segmented and registered to a standard brain template. These segmented infarcts were scaled and overlapped with published microangiographic templates, and used by 6 raters who independently estimated the branching order of arterial disease that might result in these infarcts. We used regression analysis to relate these ratings to infarct dimensions. RESULTS: Among 777 patients, there were 33 (58% male) patients with subcortical infarcts. The mean age was 63.1 ± 15.1 years. Infarct dimensions for the groups were as follows: group 1 (first-order branch): height 37.6 ± 7.4 mm, horizontal width 21.2 ± 11.6 mm, anterior-posterior length 36.8 ± 20.1 mm; group 2 (second-order branch): height 25.2 ± 7.9 mm, horizontal width 16.6 ± 22.8 mm, anterior-posterior length 16.1 ± 8.0 mm; group 3 (third-order branch): height 11.6 ± 5.7 mm, axial width 5.3 ± 3.1 mm, anterior-posterior length 5.5 ± 3.8 mm. Increasing vessel branching order (from large to small vessels) was linearly and negatively associated with infarct height (ß = -16.7 mm per change in branching order disease, 95% CI -20.3, -13.1 mm, p < 0.01) and anterior-posterior length (ß = -16.8 mm per change in branching order disease, 95% CI -23.2, -10.5 mm, p < 0.01). DISCUSSION: Based on MRI infarct dimensions and a microangiographic template, it may be possible to estimate the branching order of the artery involved in subcortical infarcts. Further, our small data set suggests that reliance on an axial dimension of 15-20 mm may not be the best approach to classifying lacunar infarct. This finding needs to be confirmed in a larger data set.


Assuntos
Artérias/patologia , Gânglios da Base/irrigação sanguínea , Infarto Cerebral/patologia , Acidente Vascular Cerebral/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Circulação Cerebrovascular/fisiologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Masculino , Pessoa de Meia-Idade
12.
Am J Physiol Regul Integr Comp Physiol ; 304(10): R818-28, 2013 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-23535460

RESUMO

An indispensable role for the brain renin-angiotensin system (RAS) has been documented in most experimental animal models of hypertension. To identify the specific efferent pathway activated by the brain RAS that mediates hypertension, we examined the hypothesis that elevated arginine vasopressin (AVP) release is necessary for hypertension in a double-transgenic model of brain-specific RAS hyperactivity (the "sRA" mouse model). sRA mice experience elevated brain RAS activity due to human angiotensinogen expression plus neuron-specific human renin expression. Total daily loss of the 4-kDa AVP prosegment (copeptin) into urine was grossly elevated (≥8-fold). Immunohistochemical staining for AVP was increased in the supraoptic nucleus of sRA mice (~2-fold), but no quantitative difference in the paraventricular nucleus was observed. Chronic subcutaneous infusion of a nonselective AVP receptor antagonist conivaptan (YM-087, Vaprisol, 22 ng/h) or the V(2)-selective antagonist tolvaptan (OPC-41061, 22 ng/h) resulted in normalization of the baseline (~15 mmHg) hypertension in sRA mice. Abdominal aortas and second-order mesenteric arteries displayed AVP-specific desensitization, with minor or no changes in responses to phenylephrine and endothelin-1. Mesenteric arteries exhibited substantial reductions in V(1A) receptor mRNA, but no significant changes in V(2) receptor expression in kidney were observed. Chronic tolvaptan infusion also normalized the (5 mmol/l) hyponatremia of sRA mice. Together, these data support a major role for vasopressin in the hypertension of mice with brain-specific hyperactivity of the RAS and suggest a primary role of V(2) receptors.


Assuntos
Pressão Sanguínea/fisiologia , Encéfalo/metabolismo , Hipertensão/metabolismo , Sistema Renina-Angiotensina/fisiologia , Vasopressinas/metabolismo , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos , Benzazepinas/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Hipertensão/genética , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Camundongos , Camundongos Transgênicos , Receptores de Vasopressinas/genética , Receptores de Vasopressinas/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Tolvaptan , Vasopressinas/genética
13.
Hypertension ; 61(3): 716-22, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23266541

RESUMO

Although elevated renin-angiotensin system activity and angiotensinergic signaling within the brain are required for hypertension, polydipsia, and increased metabolic rate induced by deoxycorticosterone acetate (DOCA)-salt, the contribution of specific receptor subtypes and brain nuclei mediating these responses remains poorly defined. We hypothesized that angiotensin type 1a receptors (AT(1a)R) within the subfornical organ (SFO) mediate these responses. Transgenic mice carrying a conditional allele of the endogenous AT(1a)R (AT(1a)R(flox)) were administered an adenovirus encoding Cre-recombinase and enhanced green fluorescent protein (eGFP) or adenovirus encoding eGFP alone into the lateral cerebral ventricle. Adenovirus encoding Cre-recombinase reduced AT(1a)R mRNA and induced recombination in AT(1a)R(flox) genomic DNA specifically in the SFO, without significant effect in the paraventricular or arcuate nuclei, and also induced SFO-specific recombination in ROSA(TdTomato) reporter mice. The effect of SFO-targeted ablation of endogenous AT(1a)R was evaluated in AT(1a)R(flox) mice at 3 time points: (1) baseline, (2) 1 week after virus injection but before DOCA-salt, and (3) after 3 weeks of DOCA-salt. DOCA-salt-treated mice with deletion of AT(1a)R in SFO exhibited a blunted increase in arterial pressure. Increased sympathetic cardiac modulation and urine copeptin, a marker of vasopressin release, were both significantly reduced in DOCA-salt mice when AT(1a)R was deleted in the SFO. Additionally, deletion of AT(1a)R in the SFO significantly attenuated the polydipsia, polyuria, and sodium intake in response to DOCA-salt. Together, these data highlight the contribution of AT(1a)R in the SFO to arterial pressure regulation potentially through changes on sympathetic cardiac modulation, vasopressin release, and hydromineral balance in the DOCA-salt model of hypertension.


Assuntos
Desoxicorticosterona/efeitos adversos , Hipertensão/induzido quimicamente , Mineralocorticoides/efeitos adversos , Receptor Tipo 1 de Angiotensina/fisiologia , Órgão Subfornical/efeitos dos fármacos , Órgão Subfornical/fisiopatologia , Animais , Pressão Arterial/efeitos dos fármacos , Biomarcadores/urina , Glicopeptídeos/urina , Coração/efeitos dos fármacos , Coração/inervação , Masculino , Camundongos , Camundongos Transgênicos , Polidipsia/induzido quimicamente , Poliúria/induzido quimicamente , Receptor Tipo 1 de Angiotensina/genética , Recombinação Genética , Sódio/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacos
14.
Nat Med ; 18(12): 1797-804, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23160237

RESUMO

Hydrocephalus is a common neurological disorder that leads to expansion of the cerebral ventricles and is associated with a high rate of morbidity and mortality. Most neonatal cases are of unknown etiology and are likely to have complex inheritance involving multiple genes and environmental factors. Identifying molecular mechanisms for neonatal hydrocephalus and developing noninvasive treatment modalities are high priorities. Here we use a hydrocephalic mouse model of the human ciliopathy Bardet-Biedl Syndrome (BBS) and identify a role for neural progenitors in the pathogenesis of neonatal hydrocephalus. We found that hydrocephalus in this mouse model is caused by aberrant platelet-derived growth factor receptor α (PDGFR-α) signaling, resulting in increased apoptosis and impaired proliferation of chondroitin sulfate proteoglycan 4 (also known as neuron-glial antigen 2 or NG2)(+)PDGFR-α(+) neural progenitors. Targeting this pathway with lithium treatment rescued NG2(+)PDGFR-α(+) progenitor cell proliferation in BBS mutant mice, reducing their ventricular volume. Our findings demonstrate that neural progenitors are crucial in the pathogenesis of neonatal hydrocephalus, and we identify new therapeutic targets for this common neurological disorder.


Assuntos
Antígenos/metabolismo , Apoptose/fisiologia , Síndrome de Bardet-Biedl/patologia , Hidrocefalia/etiologia , Células-Tronco Neurais/citologia , Proteoglicanas/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais/fisiologia , Animais , Western Blotting , Bromodesoxiuridina , Proliferação de Células/efeitos dos fármacos , Primers do DNA/genética , Feminino , Imuno-Histoquímica , Imunoprecipitação , Marcação In Situ das Extremidades Cortadas , Lítio/farmacologia , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Mutantes , Células-Tronco Neurais/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
15.
Fluids Barriers CNS ; 9(1): 22, 2012 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-23046663

RESUMO

BACKGROUND: Hydrocephalus is a heterogeneous disorder with multiple etiologies that are not yet fully understood. Animal models have implicated dysfunctional cilia of the ependyma and choroid plexus in the development of the disorder. In this report, we sought to determine the origin of the ventriculomegaly in four Bardet Biedl syndrome (BBS) mutant mouse strains as models of a ciliopathy. METHODS: Evans Blue dye was injected into the lateral ventricle of wild- type and BBS mutant mice to determine whether obstruction of intra- or extra-ventricular CSF flow contributed to ventriculomegaly. Transmission electron microscopy (TEM) was used to examine the ultrastructure of the choroid plexus, subfornical organ (SFO), subcommisural organ (SCO), and ventricular ependyma to evaluate their ultrastructure and the morphology of their primary and motile cilia. RESULTS AND DISCUSSION: No obstruction of intra- or extra-ventricular CSF flow was observed, implying a communicating form of hydrocephalus in BBS mutant mice. TEM analyses of the mutants showed no evidence of choroidal papillomas or breakdown of the blood:CSF barrier. In contrast, structural defects were observed in a subpopulation of cilia lining the choroid plexus, SFO, and ventricular ependyma. These included disruptions of the microtubular structure of the axoneme and the presence of electron-dense vesicular-like material along the ciliary shaft and at the tips of cilia. CONCLUSIONS: Abnormalities in cilia structure and function have the potential to influence ciliary intraflagellar transport (IFT), cilia maintenance, protein trafficking, and regulation of CSF production. Ciliary structural defects are the only consistent pathological features associated with CSF-related structures in BBS mutant mice. These defects are observed from an early age, and may contribute to the underlying pathophysiology of ventriculomegaly.

16.
Clin Neuropsychol ; 26(2): 335-69, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22401298

RESUMO

Focal bilateral hippocampal damage typically causes severe and selective amnesia for new declarative information (facts and events), a cognitive deficit that greatly impacts the ability to live a normal, fully independent life. We describe the case of 1846, a 48-year-old woman with profound hippocampal amnesia following status epilepticus and an associated anoxic episode at age 30. Patient 1846 has undergone extensive neuropsychological testing on many occasions over the 18 years since her injury, and we present data indicating that her memory impairment has remained severe and stable during that time. New, high-resolution, structural MRI studies of 1846's brain reveal substantial bilateral hippocampal atrophy resembling that of other well-known amnesic patients. In spite of severe amnesia 1846 lives a full and mostly independent adult life, facilitated by an extensive social support network of family and friends. Her case provides an example of a rare and unlikely positive outcome in the face of severe memory problems.


Assuntos
Amnésia/psicologia , Hipocampo/patologia , Memória , Estado Epiléptico/psicologia , Adulto , Amnésia/etiologia , Amnésia/patologia , Atrofia/patologia , Atrofia/psicologia , Feminino , Humanos , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estado Epiléptico/complicações , Estado Epiléptico/patologia
17.
Circ Res ; 108(7): 808-12, 2011 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-21311043

RESUMO

RATIONALE: The hypothalamic arcuate nucleus (ARC) is considered a major site for leptin signaling that regulates several physiological processes. OBJECTIVE: To test the hypothesis that leptin receptor in the ARC is required to mediate leptin-induced sympathetic activation. METHODS AND RESULTS: First, we used the ROSA Cre-reporter mice to establish the feasibility of driving Cre expression in the ARC in a controlled manner with bilateral microinjection of adenovirus-expressing Cre-recombinase (Ad-Cre). Ad-Cre microinjection into the ARC of ObR(flox/flox) mice robustly reduced ObR expression and leptin-induced Stat3 activation in the ARC but not in the adjacent nuclei, confirming the efficacy and selectivity of the ARC deletion of ObR. Critically, deletion of ObR in the ARC attenuated brown adipose tissue and renal sympathetic nerve responses to leptin. We also examined whether ObR in the ARC is required for the preserved leptin-induced increase in renal sympathetic activity in dietary obesity. We found that deletion of ARC ObR abrogated leptin-induced increases in renal sympathetic discharge and resolved arterial pressure elevation in diet-induced obese ObR(flox/flox) mice. CONCLUSIONS: These data demonstrate a critical role for ObR in the ARC in mediating the sympathetic nerve responses to leptin and in the adverse sympathoexcitatory effects of leptin in obesity.


Assuntos
Núcleo Arqueado do Hipotálamo/metabolismo , Deleção de Genes , Leptina/farmacologia , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacos , Adenoviridae/genética , Animais , Modelos Animais de Doenças , Proteínas de Fluorescência Verde , Homozigoto , Integrases/genética , Integrases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia
18.
Physiol Genomics ; 43(6): 286-94, 2011 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-21189370

RESUMO

The renin-angiotensin system (RAS), known for its roles in cardiovascular, metabolic, and developmental regulation, is present in both the circulation and in many individual tissues throughout the body. Substantial evidence supports the existence of a brain RAS, though quantification and localization of brain renin have been hampered by its low expression levels. We and others have previously determined that there are two isoforms of renin expressed in the brain. The classical isoform encoding secreted renin (sREN) and a novel isoform encoding intracellular renin (icREN), the product of an alternative promoter and first exon (exon 1b). The differential role that these two isoforms play in cardiovascular and metabolic regulation remains unclear. Here we examined the physiological consequences of neuron- and glia-specific knockouts of sREN by crossing mice in which the sREN promoter and isoform-specific first exon (exon-1a) is flanked by LoxP sequences (sREN(flox) mice) with mice expressing Cre-recombinase controlled by either the neuron-specific Nestin promoter or the glia-specific GFAP promoter. Resulting offspring exhibited selective knockout of sREN in either neurons or glia, while preserving expression of icREN. Consistent with a hypothesized role of icREN in the brain RAS, neuron- and glia-specific knockout of sREN had no effect on blood pressure or heart rate; food, water, or sodium intake; renal function; or metabolic rate. These data demonstrate that sREN is dispensable within the brain for normal physiological regulation of cardiovascular, hydromineral, and metabolic regulation, and thereby indirectly support the importance of icREN in brain RAS function.


Assuntos
Pressão Sanguínea/fisiologia , Encéfalo/metabolismo , Rim/metabolismo , Neuroglia/metabolismo , Neurônios/metabolismo , Sistema Renina-Angiotensina/fisiologia , Renina/fisiologia , Animais , Metabolismo Basal , Encéfalo/citologia , Éxons , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Renina/genética
19.
J Clin Exp Neuropsychol ; 32(1): 88-106, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19763994

RESUMO

We report here a case study of a rare neurological patient with bilateral brain damage encompassing a substantial portion of the so-called "limbic system." The patient, Roger, has been studied in our laboratory for over 14 years, and the current article presents his complete neuroanatomical and neuropsychological profiles. The brain damage occurred in 1980 following an episode of herpes simplex encephalitis. The amount of destroyed neural tissue is extensive and includes bilateral damage to core limbic and paralimbic regions, including the hippocampus, amygdala, parahippocampal gyrus, temporal poles, orbitofrontal cortex, basal forebrain, anterior cingulate cortex, and insular cortex. The right hemisphere is more extensively affected than the left, although the lesions are largely bilateral. Despite the magnitude of his brain damage, Roger has a normal IQ, average to above-average attention, working memory, and executive functioning skills, and very good speech and language abilities. In fact, his only obvious presenting deficits are a dense global amnesia and a severe anosmia and ageusia. Roger's case presents a rare opportunity to advance our understanding of the critical functions underlying the human limbic system, and the neuropsychological and neuroanatomical data presented here provide a critical foundation for such investigations.


Assuntos
Encefalite/patologia , Sistema Límbico/patologia , Ageusia/etiologia , Mapeamento Encefálico , Encefalite/complicações , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Transtornos do Olfato/etiologia
20.
Brain Res ; 1291: 60-72, 2009 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-19643090

RESUMO

Soluble epoxide hydrolase (sEH) is the major enzyme responsible for the metabolism and inactivation of epoxyeicosatrienoic acids (EETs). EETs are produced by the cytochrome P450 (CYP) epoxygenase pathway of arachidonic acid (AA) metabolism and tend to be anti-hypertensive, anti-inflammatory and protective against ischemic injury. Since the metabolism of EETs by sEH reduces or eliminates their bioactivity, inhibition of sEH has become a therapeutic strategy for hypertension and inflammation. sEH is found in nearly all tissues so the systemic application of inhibitors is likely to affect more than blood pressure and inflammation. In the central nervous system, EETs are thought to play a role in the regulation of local blood flow, protection from ischemic injury, inhibition of inflammation, the release of peptide hormones and modulation of fever. However, little is known about region- and cell-specific expression of sEH in the brain. In the mouse brain, expression of sEH was found widely in cortical and hippocampal astrocytes and also in a few specific neuron types in the cortex, cerebellum, and medulla. To assess the functional significance of neuronal sEH, we generated a transgenic mouse model, which over-expresses sEH specifically in neurons. Transgenic mice showed increased neuron labeling in cortex and hippocampus with little change in labeling of other brain regions. Despite a 3-fold increase in sEH activity in the brain, there was no change in arterial pressure. This data provides new information required for studying the central roles of the cytochrome P450 epoxygenase pathway.


Assuntos
Encéfalo/enzimologia , Epóxido Hidrolases/genética , Epóxido Hidrolases/metabolismo , Neurônios/enzimologia , Animais , Pressão Sanguínea/fisiologia , Western Blotting , Imunofluorescência , Vetores Genéticos , Frequência Cardíaca/fisiologia , Imuno-Histoquímica , Camundongos , Camundongos Transgênicos , Telemetria
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