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1.
Sci Rep ; 7(1): 4835, 2017 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-28684740

RESUMO

Aldosterone and the Mineralocorticoid Receptor (MR) control hydroelectrolytic homeostasis and alterations of mineralocorticoid signaling pathway are involved in the pathogenesis of numerous human diseases, justifying the need to decipher molecular events controlling MR expression level. Here, we show in renal cells that the RNA-Binding Protein, Human antigen R (HuR), plays a central role in the editing of MR transcript as revealed by a RNA interference strategy. We identify a novel Δ6 MR splice variant, which lacks the entire exon 6, following a HuR-dependent exon skipping event. Using isoform-specific TaqMan probes, we show that Δ6 MR variant is expressed in all MR-expressing tissues and cells and demonstrate that extracelullar tonicity regulates its renal expression. More importantly, this splice variant exerts dominant-negative effects on transcriptional activity of the full-length MR protein. Collectively, our data highlight a crucial role of HuR as a master posttranscriptional regulator of MR expression in response to osmotic stress. We demonstrate that hypotonicity, not only enhances MR mRNA stability, but also decreases expression of the Δ6 MR variant, thus potentiating renal MR signaling. These findings provide compelling evidence for an autoregulatory feedback loop for the control of sodium homeostasis through posttranscriptional events, likely relevant in renal pathophysiological situations.


Assuntos
Processamento Alternativo , Proteína Semelhante a ELAV 1/genética , Rim/metabolismo , Osmorregulação/genética , Receptores de Mineralocorticoides/genética , Sódio na Dieta/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Sítios de Ligação , Cristalografia por Raios X , Proteína Semelhante a ELAV 1/metabolismo , Éxons , Retroalimentação Fisiológica , Furosemida/farmacologia , Homeostase/genética , Humanos , Íntrons , Rim/efeitos dos fármacos , Camundongos , Modelos Moleculares , Concentração Osmolar , Pressão Osmótica , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Receptores de Mineralocorticoides/metabolismo , Sódio na Dieta/administração & dosagem , Homologia Estrutural de Proteína , Privação de Água , Intoxicação por Água/genética , Intoxicação por Água/metabolismo , Intoxicação por Água/fisiopatologia
2.
Neurosci Bull ; 28(6): 680-92, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23132680

RESUMO

OBJECTIVE: Aquaporin-4 (AQP4), the main water channel protein in the brain, plays a critical role in water homeostasis and brain edema. Here, we investigated its role in the inflammatory responses after focal cerebral ischemia. METHODS: In AQP4-knockout (KO) and wild-type mice, focal cerebral ischemia was induced by 30 min of middle cerebral arterial occlusion (MCAO). Ischemic neuronal injury and cellular inflammatory responses, as well as the expression and localization of cysteinyl leukotriene CysLT(2) and CysLT(1) receptors, were determined at 24 and 72 h after MCAO. RESULTS: AQP4-KO mice showed more neuronal loss, more severe microglial activation and neutrophil infiltration, but less astrocyte proliferation in the brain after MCAO than wild-type mice. In addition, the protein levels of both CysLT(1) and CysLT(2) receptors were up-regulated in the ischemic brain, and the up-regulation was more pronounced in AQP4-KO mice. The CysLT(1) and CysLT(2) receptors were primarily localized in neurons, microglia and neutrophils; those localized in microglia and neutrophils were enhanced in AQP4-KO mice. CONCLUSION: AQP4 may play an inhibitory role in postischemic inflammation.


Assuntos
Aquaporina 4/deficiência , Isquemia Encefálica/metabolismo , Inflamação/metabolismo , Receptores de Leucotrienos/biossíntese , Animais , Aquaporina 4/genética , Astrócitos/metabolismo , Western Blotting , Isquemia Encefálica/patologia , Contagem de Células , Imuno-Histoquímica , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Inflamação/patologia , Leucócitos/metabolismo , Camundongos , Camundongos Knockout , Microglia/fisiologia , Neutrófilos/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Regulação para Cima , Intoxicação por Água/metabolismo
3.
Neuropathology ; 31(3): 250-64, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21118399

RESUMO

Hypotonicity following water intoxication and/or salt loss leads to mainly astrocytic brain swelling. Astrocytic swelling also occurs following brain trauma or ischemia, together with an increase in extracellular K(+) ([K(+)](o)), stimulating a bumetanide/furosemide/ethacrynic acid-inhibitable cotransporter, NKCC1, that accumulates Na(+) and K(+) together with 2 Cl(-) and osmotically obliged water. Either type of swelling may become fatal and is associated with phosphorylation of extracellular regulated kinases 1 and 2 (ERK(1/2)). Only the swelling associated with elevated [K(+)](o), leads to an increase in astrocytic proliferation and in expression of the astrocytic marker, glial fibrillary acidic protein. These differences prompted us to investigate key aspects of the molecular pathways between hypotonicity-induced and high-K(+)-mediated swelling in primary cultures of mouse astrocytes. In the latter Ca(2+)-mediated, AG1478-inhibitable transactivation of the epidermal growth factor (EGF) receptor leads, via bumetanide-inhibitable activation of the mitogen activated protein (MAP) kinase pathway to ERK phosphorylation and to NKCC1-mediated swelling. In the former, inhibition of the MAP kinase pathway, but not of EGF receptor activation, abolishes ERK phosphorylation, but has no effect on swelling, indicating that activation of ERK is a result, not a cause, of the swelling.


Assuntos
Astrócitos/metabolismo , Astrócitos/patologia , Edema Encefálico/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Intoxicação por Água/metabolismo , Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Proteína ADAM17 , Animais , Astrócitos/efeitos dos fármacos , Edema Encefálico/patologia , Bumetanida/farmacologia , Divisão Celular/fisiologia , Células Cultivadas , Quelantes/farmacologia , Ácido Egtázico/análogos & derivados , Ácido Egtázico/farmacologia , Receptores ErbB/metabolismo , Fator de Crescimento Semelhante a EGF de Ligação à Heparina , Soluções Hipotônicas/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , MAP Quinase Quinase Quinase 1/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Fosforilação/fisiologia , Potássio/farmacologia , RNA Interferente Pequeno , Inibidores de Simportadores de Cloreto de Sódio e Potássio/farmacologia , Intoxicação por Água/patologia , Quinases da Família src/antagonistas & inibidores
4.
Pediatr Nephrol ; 22(6): 778-84, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17347837

RESUMO

Aquaporin-4 (AQP4) is a water-channel protein expressed strongly in the brain, predominantly in astrocyte foot processes at the borders between the brain parenchyma and major fluid compartments, including cerebrospinal fluid (CSF) and blood. This distribution suggests that AQP4 controls water fluxes into and out of the brain parenchyma. Experiments using AQP4-null mice provide strong evidence for AQP4 involvement in cerebral water balance. AQP4-null mice are protected from cellular (cytotoxic) brain edema produced by water intoxication, brain ischemia, or meningitis. However, AQP4 deletion aggravates vasogenic (fluid leak) brain edema produced by tumor, cortical freeze, intraparenchymal fluid infusion, or brain abscess. In cytotoxic edema, AQP4 deletion slows the rate of water entry into brain, whereas in vasogenic edema, AQP4 deletion reduces the rate of water outflow from brain parenchyma. AQP4 deletion also worsens obstructive hydrocephalus. Recently, AQP4 was also found to play a major role in processes unrelated to brain edema, including astrocyte migration and neuronal excitability. These findings suggest that modulation of AQP4 expression or function may be beneficial in several cerebral disorders, including hyponatremic brain edema, hydrocephalus, stroke, tumor, infection, epilepsy, and traumatic brain injury.


Assuntos
Aquaporina 4/metabolismo , Edema Encefálico/metabolismo , Animais , Aquaporina 4/deficiência , Aquaporina 4/genética , Edema Encefálico/etiologia , Edema Encefálico/patologia , Modelos Animais de Doenças , Humanos , Hidrocefalia/etiologia , Hidrocefalia/metabolismo , Hidrocefalia/patologia , Hiponatremia/complicações , Hiponatremia/metabolismo , Hiponatremia/fisiopatologia , Camundongos , Camundongos Knockout , Água/metabolismo , Intoxicação por Água/metabolismo , Intoxicação por Água/patologia , Intoxicação por Água/fisiopatologia
5.
Biochim Biophys Acta ; 1758(8): 1085-93, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16564496

RESUMO

Aquaporin-4 (AQP4) is expressed in astrocytes throughout the central nervous system, particularly at the blood-brain and brain-cerebrospinal fluid barriers. Phenotype analysis of transgenic mice lacking AQP4 has provided compelling evidence for involvement of AQP4 in cerebral water balance, astrocyte migration, and neural signal transduction. AQP4-null mice have reduced brain swelling and improved neurological outcome in models of (cellular) cytotoxic cerebral edema including water intoxication, focal cerebral ischemia, and bacterial meningitis. However, brain swelling and clinical outcome are worse in AQP4-null mice in models of vasogenic (fluid leak) edema including cortical freeze-injury, brain tumor, brain abscess and hydrocephalus, probably due to impaired AQP4-dependent brain water clearance. AQP4 deficiency or knock-down slows astrocyte migration in response to a chemotactic stimulus in vitro, and AQP4 deletion impairs glial scar progression following injury in vivo. AQP4-null mice also manifest reduced sound- and light-evoked potentials, and increased threshold and prolonged duration of induced seizures. Impaired K+ reuptake by astrocytes in AQP4 deficiency may account for the neural signal transduction phenotype. Based on these findings, we propose modulation of AQP4 expression or function as a novel therapeutic strategy for a variety of cerebral disorders including stroke, tumor, infection, hydrocephalus, epilepsy, and traumatic brain injury.


Assuntos
Aquaporina 4/fisiologia , Edema Encefálico/fisiopatologia , Encéfalo/fisiopatologia , Potenciais de Ação , Animais , Astrócitos/fisiologia , Barreira Hematoencefálica , Encéfalo/metabolismo , Encéfalo/patologia , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Lesões Encefálicas/fisiopatologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/fisiopatologia , Quimiotaxia , Potenciais Evocados , Hidrocefalia/metabolismo , Hidrocefalia/patologia , Hidrocefalia/fisiopatologia , Meningites Bacterianas/metabolismo , Meningites Bacterianas/patologia , Meningites Bacterianas/fisiopatologia , Camundongos , Camundongos Knockout , Convulsões/metabolismo , Convulsões/patologia , Convulsões/fisiopatologia , Transdução de Sinais , Intoxicação por Água/metabolismo , Intoxicação por Água/patologia , Intoxicação por Água/fisiopatologia
6.
Expert Opin Investig Drugs ; 11(11): 1553-62, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12437502

RESUMO

Adenosine is a vasoactive hormone whose action is mediated through at least four receptors. The most prevalent receptors are type 1, which promote vasoconstriction, and type 2, comprised of 2 subtypes (a,b) that promote vasodilation. In the kidney, type 1 receptors located on preglomerular vessels and in the tubule are involved in the regulation of glomerular filtration. Whole body fluid balance is strongly dependent on the ability of the kidney to maintain stable glomerular filtration. Several antagonists to adenosine type 1 receptors have been developed. These agents generate excess fluid (diuresis) and sodium (natriuresis) excretion in control animals and animal models of fluid retention, as well as in normal and oedematous humans. In both animals and humans, these effects are generally achieved without major changes in glomerular filtration. Animal studies have confirmed the location of adenosine type 1 receptors in relevant tissue sites in the kidney. More highly selective antagonists for adenosine type 1 receptors are regularly developed, improving their use in fluid retaining disorders. Clinical trials with these agents have commenced for the treatment of hypertension, renal failure and congestive heart failure, all disorders that include varying levels of fluid retention. The clinical trial results have been mixed. The early results with congestive heart failure suggest great promise for these agents, whereas trials in hypertension and renal failure have been equivocal.


Assuntos
Líquidos Corporais/efeitos dos fármacos , Edema/tratamento farmacológico , Antagonistas de Receptores Purinérgicos P1 , Equilíbrio Hidroeletrolítico/efeitos dos fármacos , Animais , Líquidos Corporais/fisiologia , Edema/metabolismo , Edema/fisiopatologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Receptores Purinérgicos P1/metabolismo , Intoxicação por Água/tratamento farmacológico , Intoxicação por Água/metabolismo , Equilíbrio Hidroeletrolítico/fisiologia
7.
J Neurosci Res ; 62(5): 750-3, 2000 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-11104514

RESUMO

To understand the increased susceptibility of the development of serious complications to hypoosmotic hyponatremia in young females, we examined the resistance of blood brain barrier (BBB) permeability to water along with the synaptosomal Na(+),K(+)ATPase activity in both sexes of rats during acute water intoxication. Four groups of rats were used: Group I and II were normal female and male rats injected with only Evans-blue. Group III and IV were water intoxicated female and male rats respectively. BBB permeability in female rats was found to be increased following acute water intoxication. In contrast, synaptosomal Na(+),K(+)ATPase activities in both water intoxicated male and female rats were found significantly lower than those in control rats. But inhibition in enzyme activity in synaptosomes from water intoxicated female rats was more pronounced than those of corresponding male rats. Our results concluded that female sex steroids may be responsible for the highly significant decrease in synaptosomal Na(+),K(+)ATPase activity and increased BBB permeability in female rats following water intoxication.


Assuntos
Barreira Hematoencefálica , ATPase Trocadora de Sódio-Potássio/metabolismo , Intoxicação por Água/metabolismo , Doença Aguda , Animais , Transporte Biológico , Feminino , Masculino , Concentração Osmolar , Permeabilidade , Ratos , Ratos Wistar , Fatores Sexuais , Intoxicação por Água/sangue
8.
Aust N Z J Psychiatry ; 31(6): 869-73, 1997 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-9483261

RESUMO

OBJECTIVE: The aim of this study was to determine the prevalence of polydipsia-hyponatremia among patients with schizophrenia in an Asian mental hospital. METHOD: Seven hundred and twenty-eight inpatients with schizophrenia were assessed for polydipsia-hyponatremia using case notes reviews, specific gravity of urine, normalised diurnal weight gain, and serum sodium levels. RESULTS: One hundred and three (13.8%) patients had polydipsia, 30 (4.1%) had polydipsia-hyponatremia and 14 (1.9%) had a history of water intoxication. Eight of the 30 patients were receiving carbamazepine, three were on tricyclic antidepressants and two had diabetes mellitus and were on sulfonylureas. CONCLUSION: The prevalence of water intoxication among polydipsic patients was low compared to Western studies. This could be due to different methods of assessing polyuria, or ethnic differences and/or the prohibition of smoking in our patients. Certain medications might have also contributed to hyponatremia.


Assuntos
Etnicidade/estatística & dados numéricos , Esquizofrenia/diagnóstico , Desequilíbrio Hidroeletrolítico/diagnóstico , Adulto , Idoso , Ritmo Circadiano , Comorbidade , Comparação Transcultural , Ingestão de Líquidos , Feminino , Hospitalização , Hospitais Psiquiátricos , Humanos , Hiponatremia/diagnóstico , Hiponatremia/epidemiologia , Hiponatremia/metabolismo , Masculino , Pessoa de Meia-Idade , Poliúria/diagnóstico , Poliúria/epidemiologia , Prevalência , Esquizofrenia/epidemiologia , Esquizofrenia/metabolismo , Singapura/epidemiologia , Intoxicação por Água/diagnóstico , Intoxicação por Água/epidemiologia , Intoxicação por Água/metabolismo , Desequilíbrio Hidroeletrolítico/epidemiologia , Desequilíbrio Hidroeletrolítico/metabolismo , Aumento de Peso
10.
Acta Neurochir (Wien) ; 41(4): 273-86, 1978.
Artigo em Inglês | MEDLINE | ID: mdl-685738

RESUMO

Different degrees of severity in global brain oedema were induced by varying amounts of water intoxication (50, 100, 150, and 200 ml Aqua dest./kg b.wt. intravenously) in groups of six cats, which were functionally nephrectomized. Animals loaded with physiological saline and sham-operated served as controls. Two hours following the water load, the tissue concentrations of CrP, ATP, ADP, AMP, pyruvate, glucose, and lactate were determined by optical enzymatic analysis. The results show disturbances in brain energy metabolism dependent on the severity of the brain oedema. The high energy compounds and in consequence the ATP/ADP-ratio, and respectively the energy charge potential, fall in direct relationship to the severity of the brain oedema. Lactate and lactate-pyruvate ratio increase. The energy source of the cell, glucose as well as pyruvate, significantly falls in the group with severe brain oedema. The results of the brain energy metabolism were compared with our previous study concerning the brain water content, rCBF and CPP in global brain oedema (Meinig et al. 1973). The results show that the disturbances of energy metabolism are directly related to the rCBF and are not dependent on CPP over a wide range.


Assuntos
Edema Encefálico/metabolismo , Encéfalo/metabolismo , Metabolismo Energético , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Gatos , Circulação Cerebrovascular , Intoxicação por Água/metabolismo
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