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1.
Nephron ; 146(4): 393-403, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34942618

RESUMO

BACKGROUND: DBA/2FG-pcy (pcy) mice harbor a homozygous Nphp3 missense mutation and develop nephronophthisis with renal interstitial fibrosis. Previous studies have shown that aberrant oxygen homeostasis contributes to the renal pathology in pcy mice, but the underlying molecular mechanism remains largely unknown. METHODS: pcy mice and a control strain, DBA/2N (DBA) mice, were used. Renal levels of 62 mRNAs involved in oxygen homeostasis were investigated by real-time PCR, and the resulting data were used for extraction of pathological pathways. On the basis of the genes found to be upregulated and pathway analysis, further studies were performed using immunoblotting, immunohistochemistry, and pharmacological intervention. RESULTS: In comparison with DBA mice, the levels of 18 mRNAs were altered by >2-fold in pcy mice. Pathway analysis extracted molecular pathways related to oxidative stress, inflammation, and cell adhesion. As the levels of mRNAs relevant to the NADPH oxidase 2 (NOX2) pathway were prominently (4 genes >5-fold) increased in pcy mice, we further analyzed the molecules related to this pathway. A time course study suggested that the pathway was gradually activated in pcy mice from at least 5 weeks of age. Immunohistochemistry study revealed that NOX2 protein was colocalized with a macrophage marker protein in the renal interstitium. Moreover, treatment of pcy mice with apocynin, an inhibitor of the NOX2 pathway, ameliorated the renal fibrosis. CONCLUSION: Our findings suggest that the activation of the NOX2 pathway, possibly mediated by macrophage infiltration, plays a pivotal role in progressive renal fibrosis in pcy mice.


Assuntos
NADPH Oxidase 2/metabolismo , Doenças Renais Policísticas , Animais , Fibrose , Camundongos , Camundongos Endogâmicos DBA , Modelos Teóricos , NADPH Oxidase 2/genética , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Oxigênio/metabolismo , Doenças Renais Policísticas/genética , RNA Mensageiro/genética , Regulação para Cima
2.
Sleep Med ; 85: 138-146, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34329897

RESUMO

OBJECTIVE: Restless legs syndrome (RLS) is a sensorimotor disorder that is characterized by uncomfortable and unpleasant sensations mainly in the legs. Two placebo-controlled studies (Phase II/III and post-marketing) in Japanese patients with RLS failed to demonstrate the efficacy of gabapentin enacarbil (GE) 600 mg in the change from baseline in International Restless Legs Syndrome Rating Scale (IRLS) score at the end of the treatment period. The high response to placebo is thought to be a possible reason why the post-marketing study failed. The objectives of these post hoc analyses were to determine potential predictive factors associated with improvement in IRLS score with GE treatment and to identify subgroups with higher placebo responses. METHODS: We combined data from the two Japanese studies and analyzed change from baseline in IRLS score in the pooled population and subgroups defined by several patient characteristics. Moreover, we calculated the variable importance of each factor and performed predictive enrichment analysis to identify an enrichable subpopulation with greater improvement by GE treatment. RESULTS: The post hoc analyses suggested that higher baseline IRLS score (≥21) and higher body mass index (≥25 kg/m2) were associated with higher placebo responses. On the other hand, positive family history of RLS, prior use of dopaminergic receptor agonists, and higher baseline ferritin level (≥50 ng/mL) were associated with higher responses to GE. CONCLUSIONS: Our results suggest that patients with typical idiopathic RLS characteristics, including positive family history and no low ferritin level, would be expected to derive the greatest benefits from GE treatment.


Assuntos
Síndrome das Pernas Inquietas , Carbamatos/uso terapêutico , Método Duplo-Cego , Humanos , Japão , Síndrome das Pernas Inquietas/tratamento farmacológico , Resultado do Tratamento , Ácido gama-Aminobutírico/análogos & derivados
3.
Physiol Rep ; 7(9): e14092, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31074077

RESUMO

The DBA/2-FG pcy (pcy) mouse is a model of human nephronophthisis, a recessive cystic kidney disease. Renal expression of aquaporin-2 (AQP2), a water channel protein, has been shown to be altered in pcy mice. However, the relationship between the renal expression and its release in urinary extracellular vesicles (uEV-AQP2), which account for most urinary AQP2, in pcy mice has remained largely unknown. In this study, we examined age-related alterations of this relationship in pcy mice. In comparison with control mice, pcy mice after the age of 14 weeks showed defective urinary concentration ability with an increase in urinary volume. Interestingly, the release of uEV-AQP2 increased progressively up to the age of 16 weeks, but at 21 weeks the release did not significantly differ from that in control mice (i.e., a bell-shaped pattern was evident). Similar results were obtained for uEV marker proteins, including tumor susceptibility gene 101 (TSG101) protein and apoptosis-linked gene 2-interacting protein X (Alix). Immunoblot analysis revealed that renal AQP2 expression increased progressively from 11 weeks, and immunohistochemistry showed that this increase was possibly due to an increase in the number of AQP2-positive cells. Analysis of mRNAs for seven types of AQP expressed in the kidney supported this notion. These data suggest that the level of uEV-AQP2 does not simply mirror the renal expression of AQP2 and that the altered release of uEV-AQP2 in pcy mice depends on the numbers of both renal AQP2-positive cells and EVs released into the urine.


Assuntos
Aquaporina 2/urina , Vesículas Extracelulares/metabolismo , Doenças Renais Císticas/congênito , Envelhecimento/genética , Envelhecimento/metabolismo , Envelhecimento/fisiologia , Animais , Aquaporina 2/genética , Aquaporina 2/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Regulação da Expressão Gênica/fisiologia , Rim/metabolismo , Doenças Renais Císticas/metabolismo , Camundongos Endogâmicos DBA , Camundongos Mutantes , RNA Mensageiro/genética , Fatores de Transcrição/metabolismo
4.
Biochem Biophys Rep ; 17: 169-176, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30656220

RESUMO

Aquaporin-11 (AQP11) is an intracellular AQP. Several studies with Aqp11 -/- mice have shown that AQP11 has a role in normal development of the kidney after birth. Our previous studies have suggested that alteration of oxygen homeostasis may be involved in the kidney injury caused by AQP11 deficiency, although the underlying mechanism is largely unknown. To clarify this issue, we examined genes that are related to oxygen homeostasis in Aqp11 -/- mice. Among 62 genes that are involved in oxygen homeostasis, 35 were upregulated by more than 2-fold in Aqp11 -/- mice in comparison with wild-type mice. Pathway analysis using these genes extracted the pathway responsible for production of reactive oxygen species in macrophages. As expression of the genes involved in the NADPH oxidase 2 (NOX2) complex was dramatically increased by more than 14-fold, we further analyzed NOX2 at the protein level. Immunoblotting analysis demonstrated a dramatic increase of NOX2 protein in the kidney of Aqp11 -/- mice, and immunohistochemistry showed that NOX2 protein and a marker protein for macrophages were increased in the renal interstitium. These results indicate that NOX2-induced oxidative stress accompanied by macrophage infiltration plays an important role in alteration of oxygen homeostasis in Aqp11 -/- mice.

5.
Am J Physiol Renal Physiol ; 314(4): F584-F601, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29357442

RESUMO

Acute kidney injury (AKI) is an important risk factor for the development of chronic kidney disease (CKD), and an alteration in renal water handling has been observed during the transition of AKI to CKD. Urinary exosomal release of aquaporin-1 (AQP1) and AQP2, important proteins for renal water handling, has recently been reported to predict their levels of renal expression. Therefore, we examined the patterns of urinary exosomal release of AQP1 and AQP2, and the exosomal marker proteins tumor susceptibility 101 protein (TSG101) and ALG-2 interacting protein X (Alix), in the acute and chronic phases following induction of AKI by renal bilateral ischemia/reperfusion (I/R) in rats. Blood tests and histological examinations indicated that AKI occurred before at 7 days after renal I/R ( day 7) and that renal fibrosis developed progressively thereafter. Immunoblotting demonstrated significant decreases in the urinary exosomal release of AQP1 and AQP2 during severe AKI. Urinary exosomal release of Alix and TSG101 was significantly increased on day 7. These data were also confirmed in rats with unilateral renal I/R causing more serious AKI. Urinary exosomal release of either the Ser-256- or Ser-269-phosphorylated form of AQP2, both of which are involved in apical trafficking of AQP2, was positively correlated with that of total AQP2. These results suggest that urinary exosomal release of AQP1 and AQP2 is reduced in I/R-induced AKI, whereas that of Alix and TSG101 is increased in the initial phase of renal fibrosis. Furthermore, apical trafficking of AQP2 appears to be related to urinary exosomal release of AQP2.


Assuntos
Injúria Renal Aguda/urina , Aquaporina 1/urina , Aquaporina 2/urina , Exossomos/metabolismo , Rim/metabolismo , Eliminação Renal , Traumatismo por Reperfusão/urina , Injúria Renal Aguda/patologia , Animais , Proteínas de Ligação ao Cálcio/urina , Proteínas de Ligação a DNA/urina , Modelos Animais de Doenças , Complexos Endossomais de Distribuição Requeridos para Transporte/urina , Fibrose , Rim/patologia , Masculino , Fosforilação , Transporte Proteico , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologia , Fatores de Tempo , Fatores de Transcrição/urina
6.
Nephrol Dial Transplant ; 31(10): 1623-32, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27190370

RESUMO

BACKGROUND: Renal aquaporin-1 (AQP1), a water channel protein, is known to be secreted into urine, conveyed by nano-sized extracellular vesicles called exosomes. A previous study has demonstrated that acetazolamide (AZ), a diuretic that inhibits carbonic anhydrases, alters the expression level of AQP1 in cultured cells. Here we investigated whether AZ alters the release of urinary exosomal AQP1 in vivo. METHODS: The effect of AZ on urinary exosomal AQP1 secretion was examined in rats and compared with furosemide (another diuretic), NaHCO3 (an alkalizing agent) and NH4Cl (an acidifying agent). Urine, blood and kidney samples were obtained 2 h after each treatment. Urinary exosomes were isolated by a differential centrifugation technique and urinary exosomal proteins were analyzed by immunoblotting. RESULTS: The release of exosomal AQP1 into urine was markedly increased after treatment with AZ, accompanied by alkaluria and metabolic acidosis. Immunohistochemistry clearly demonstrated that AZ increased the apical membrane expression of AQP1 in the proximal tubules. AZ did not affect the release of exosomal marker proteins (tumor susceptibility gene 101 protein and apoptosis-linked gene 2 interacting protein X). Treatment with furosemide did not change, whereas NaHCO3 and NH4Cl decreased the exosomal release of AQP1. CONCLUSION: The present findings indicate that AZ increases the release of exosomal AQP1 into urine in association with enhanced apical membrane expression of AQP1.


Assuntos
Acetazolamida/farmacologia , Aquaporina 1/urina , Diuréticos/farmacologia , Animais , Avaliação Pré-Clínica de Medicamentos , Exossomos/metabolismo , Furosemida/farmacologia , Concentração de Íons de Hidrogênio , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Ratos Sprague-Dawley
7.
Neurologist ; 18(4): 211-3, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22735249

RESUMO

INTRODUCTION: Although poststroke dementia has been investigated, patients with mild cognitive impairment (MCI) after stroke have received less attention, especially if there is cognitive decline in the absence of focal stroke symptoms. CASE REPORT: We report an 80-year-old female referred to our memory clinic with a 6-month history of amnestic symptoms. Neuropsychological evaluation demonstrated a marked decline in short-term memory, without anosognosia, aphasia, motor deficit, or sensory disturbance. A brain magnetic resonance imaging performed 2 months after the onset of her symptoms revealed a lacunar infarction in the genu of the right internal capsule extended to the anterior thalamus. This lesion had not been present in a previous magnetic resonance imaging obtained 2 months before her amnestic symptoms appeared. CONCLUSIONS: The patient reported here demonstrated the evolution of MCI in the setting of a newly emergent lacunar infarction in the genu of the right internal capsule extended to the anterior thalamus. One possible mechanism for amnestic symptoms from a lacunar infarct in this location might be thalamocortical disconnection leading to "strategic-infarct MCI."


Assuntos
Disfunção Cognitiva/etiologia , Acidente Vascular Cerebral Lacunar/complicações , Acidente Vascular Cerebral Lacunar/patologia , Idoso de 80 Anos ou mais , Feminino , Humanos , Imageamento por Ressonância Magnética , Testes Neuropsicológicos , Tomografia Computadorizada de Emissão de Fóton Único
8.
Brain Nerve ; 60(9): 1061-5, 2008 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-18807940

RESUMO

Here, we report the case of a 23-year-old man with type 1 renal tubular acidosis (RTA) associated with osmotic demyelination syndrome (ODS) who developed pontine hemorrhage. Acute progressive tetraparesis had developed during the clinical course of the RTA. Neurological examination revealed bilateral weakness in all 4 limbs associated with severe hypokalemia (K 1.4 mEq/L). He experienced a sudden onset of general convulsions and mutism during the treatment for metabolic acidosis and hypokalemia. The T2-weighted MR image of the brain revealed multiple hyperintense signal lesions in the central pons as well as in the extrapontine sites of the bilateral cortical and subcortical areas in the frontal and parietal lobes. A T2-star (T2*)-weighted MR image showed focal hemorrhagic lesions in the lower pons. On the basis of the diagnosis of ODS, he underwent corticosteroid and thyrotropin-releasing hormone therapy, after which his neurological signs and symptoms have gradually reduced. While analyzing the possible etiology, it has been suggested that osmotic vascular injuries induced by elevated levels of serum potassium and osmolarity give rise to edema and vascular endothelial damage; these conditions, consequently lead to hemorrhagic necrosis. Physicians need to be aware that RTA patients may develop ODS after hypokalemia, and the potassium levels need to be corrected carefully. (Received: November 6, 2007, Accepted: June 11, 2008)


Assuntos
Acidose Tubular Renal/complicações , Hemorragia Cerebral/etiologia , Doenças Desmielinizantes/etiologia , Ponte , Adulto , Hemorragia Cerebral/diagnóstico , Doenças Desmielinizantes/tratamento farmacológico , Humanos , Hipopotassemia/etiologia , Imageamento por Ressonância Magnética , Masculino , Metilprednisolona/administração & dosagem , Mielinólise Central da Ponte/etiologia , Concentração Osmolar , Síndrome , Hormônio Liberador de Tireotropina/administração & dosagem , Resultado do Tratamento
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