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1.
Cell Tissue Res ; 387(2): 303-314, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34837110

RESUMO

Renal α2-adrenoceptors have been reported to play a role in the regulation of urinary output, renin secretion, and water and sodium excretion in the kidneys. However, the distribution of α2-adrenoceptor subtypes in the kidneys remains unclear. In this study, we aimed to investigate the localization of α2-adrenoceptor subtypes in rat kidneys using 8-week-old Sprague-Dawley rats. Immunofluorescence imaging revealed that both α2A- and α2B-adrenoceptors were expressed in the basolateral, but not apical, membrane of the epithelial cells of the proximal tubules. We also found that α2A- and α2B-adrenoceptors were not expressed in the glomeruli, collecting ducts, or the descending limb of the loop of Henle and vasa recta. In contrast, α2C-adrenoceptors were found to be localized in the glomeruli and lumen of the cortical and medullary collecting ducts. These results suggest that noradrenaline may act on the basement membrane of the proximal tubules through α2A- and α2B-adrenoceptors. Moreover, noradrenaline may be involved in the regulation of glomerular filtration and proteinuria through the induction of morphological changes in mesangial cells and podocytes via α2C-adrenoceptors. In the collecting ducts, urinary noradrenaline may regulate morphological changes of the microvilli through α2C-adrenoceptors. Our findings provide an immunohistochemical basis for understanding the cellular targets of α2-adrenergic regulation in the kidneys. This may be used to devise therapeutic strategies targeting α2-adrenoceptors.


Assuntos
Receptores Adrenérgicos alfa 2 , Roedores , Animais , Rim , Norepinefrina , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa 2/fisiologia
2.
J Pharmacol Sci ; 145(1): 79-87, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33357783

RESUMO

In the present study, we investigated the renoprotective effects of long-term treatment with yohimbine, an α2-adrenoceptor inhibitor, in a 5/6 nephrectomy-induced chronic kidney disease (CKD) rat model. Male Sprague-Dawley rats were randomly allocated into the following groups: sham-operated, 5/6-nephrectomized (5/6 Nx), 5/6 Nx + low or high dose of yohimbine (0.3 or 3.0 mg/L in drinking water, respectively), and 5/6 Nx + hydralazine (250 mg/L in drinking water). The 5/6 Nx group presented with renal dysfunction, hypertension, noradrenaline overproduction, and histopathological injuries. Blood pressure decreased in both the yohimbine- and hydralazine-treated groups. Treatment with high dose of yohimbine, but not hydralazine, apparently attenuated urinary protein excretion and noradrenaline concentration of renal venous plasma. Renal fibrosis and upregulated fibrosis-related gene expression were suppressed by high dose of yohimbine. Furthermore, yohimbine, but not hydralazine, treatment ameliorated the urinary concentration ability. These findings suggest that long-term yohimbine treatment can be a useful therapeutic option to prevent the progression of CKD.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Nefrectomia/efeitos adversos , Insuficiência Renal Crônica/prevenção & controle , Ioimbina/administração & dosagem , Animais , Vesícula/patologia , Modelos Animais de Doenças , Progressão da Doença , Epidermólise Bolhosa/patologia , Fibrose , Hidralazina/administração & dosagem , Masculino , Norepinefrina/metabolismo , Doenças Periodontais/patologia , Transtornos de Fotossensibilidade/patologia , Proteinúria/etiologia , Proteinúria/prevenção & controle , Ratos Sprague-Dawley , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/fisiopatologia
3.
Eur J Pharmacol ; 871: 172917, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31935395

RESUMO

Sepsis-induced acute kidney injury (AKI) is frequently observed in the intensive care unit. We previously revealed that yohimbine, an α2-adrenoceptor antagonist, has protective effects on renal ischemia/reperfusion injury-induced AKI in rats. This study aimed to investigate the renoprotective effect of yohimbine on lipopolysaccharide (LPS)-induced AKI in rats. Male Sprague Dawley rats were randomly divided into the following groups: Sham-operated group, LPS (10 mg/kg, i.p.) and LPS + yohimbine (0.1 or 0.5 mg/kg, i.p.). Kidney functional parameters of blood urea nitrogen (BUN) and plasma creatinine (Pcr) were aggravated in the LPS group. Administration of LPS decreased blood pressure. In addition, kidney injury molecule-1, inducible nitric oxide synthase (iNOS) and expression of various cytokines such as tumour necrosis factor-α, monocyte chemoattractant protein-1, and interleukin (IL)-6 were increased by LPS administration. Yohimbine treatment clearly ameliorated the damaged kidney function and low blood pressure due to LPS. Moreover, yohimbine suppressed cytokine mRNA and iNOS expression enhanced by LPS. However, anti-inflammatory cytokine IL-10 mRNA levels were augmented by yohimbine. Nuclear localization of nuclear factor-kappa B (NF-κB) in the kidney was observed 1 h after injection of LPS in rats. Yohimbine blocked the nuclear localization of NF-κB. In addition, phosphorylation of extracellular signal-regulated kinase (ERK) and cAMP response element binding protein (CREB) were enhanced with yohimbine. These results suggest that yohimbine can prevent LPS-induced sepsis associated with kidney injury by suppressing inflammatory cytokine and iNOS expression as well as enhancing IL-10 expression via ERK/CREB phosphorylation.


Assuntos
Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Lipopolissacarídeos/farmacologia , Ioimbina/farmacologia , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Injúria Renal Aguda/metabolismo , Animais , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Masculino , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Ioimbina/uso terapêutico
4.
J Pharmacol Sci ; 139(3): 137-142, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30665845

RESUMO

Ischemia/reperfusion injury is the most common cause of acute kidney injury. We previously revealed that pre-treatment with yohimbine or JP-1302 attenuated renal ischemia/reperfusion injury by inhibition of α2C-adrenoceptor antagonist. The aim of the present study is to investigate the effects of post-treatment with JP-1302 on renal ischemia/reperfusion injury in rats. Male Sprague Dawley rats were randomly divided into four groups: sham operation, ischemia/reperfusion, pre-treatment with JP-1302 (3.0 mg/kg) and post-treatment with JP-1302 groups. In ischemia/reperfusion injury, renal functional parameters, such as blood urea nitrogen, plasma creatinine and creatinine clearance, deteriorated after reperfusion. Renal venous norepinephrine concentrations, as well as inflammatory molecules in the kidney increased after reperfusion. Both pre- and post-treatment with JP-1302 improved renal dysfunction, tissue damage, renal venous norepinephrine concentrations and inflammatory molecules expression in the kidney. In conclusion, these results suggest that post-treatment with JP-1302 protects on ischemia/reperfusion-induced acute kidney injury by suppressing cytokine upregulation via α2C-adrenoceptors.


Assuntos
Acridinas/farmacologia , Injúria Renal Aguda/prevenção & controle , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Piperazinas/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Acridinas/administração & dosagem , Antagonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Animais , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Citocinas/metabolismo , Esquema de Medicação , Masculino , Piperazinas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/metabolismo , Traumatismo por Reperfusão/complicações , Regulação para Cima/efeitos dos fármacos
5.
Eur J Pharmacol ; 838: 113-119, 2018 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-30201375

RESUMO

Nephrotoxicity is a major adverse reaction of the anticancer drug, cisplatin. We investigated the renoprotective effects of the α2-adrenoceptor antagonist, yohimbine and selective α2C-adrenoceptor antagonist, JP-1302, in cisplatin-treated Sprague Dawley rats. Rats were given a single intravenous dose of 7.5 mg/kg cisplatin and then yohimbine or JP-1302 was administered intraperitoneally at 0.1 or 3 mg/kg/day, respectively, for four days. Renal functional parameters, such as blood urea nitrogen, plasma creatinine, creatinine clearance and renal venous norepinephrine concentrations were measured. Kidney tissue damage and tumour necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) mRNA levels were assessed after the animals were euthanized. Cisplatin treatment aggravated the kidney functional parameters of blood urea nitrogen, plasma creatinine and creatinine clearance. Renal venous norepinephrine concentrations were also elevated after cisplatin administration. Treatment with yohimbine or JP-1302 clearly ameliorated kidney function and cell apoptosis. These treatments suppressed elevated renal plasma norepinephrine, TNF-α, MCP-1 and cleaved caspase 3 expressions which occurred after administration of cisplatin. These results suggest that yohimbine can prevent cisplatin-induced renal toxicity associated with acute kidney injury by suppressing cytokine expression through α2C-adrenoceptors.


Assuntos
Acridinas/farmacologia , Injúria Renal Aguda/tratamento farmacológico , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Cisplatino/efeitos adversos , Piperazinas/farmacologia , Ioimbina/farmacologia , Acridinas/uso terapêutico , Injúria Renal Aguda/sangue , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/patologia , Antagonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Quimiocina CCL2/metabolismo , Modelos Animais de Doenças , Injeções Intraperitoneais , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Norepinefrina/sangue , Piperazinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa 2/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ioimbina/uso terapêutico
6.
Eur J Pharmacol ; 818: 38-42, 2018 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-29032106

RESUMO

Increases in renal sympathetic nerve activity during ischaemia and renal venous norepinephrine levels after reperfusion play important roles in the development of ischaemia/reperfusion-induced acute kidney injury. In the present study, we examined the effect of isatin, an endogenous monoamine oxidase inhibitor, on renal venous norepinephrine levels, superoxide production after reperfusion, and ischaemia/reperfusion-induced acute kidney injury. Ischaemia/reperfusion-induced acute kidney injury was accomplished by clamping the left renal artery and vein for 45min, followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal superoxide production and norepinephrine overflow were elevated and significant renal tissue damage was observed following ischaemia/reperfusion injury. Intravenous injection of isatin (10mg/kg) at 5min before ischaemia increased the renal venous plasma norepinephrine level after reperfusion and aggravated ischaemia/reperfusion-induced renal dysfunction and histological damage. The excessive superoxide production after reperfusion was significantly suppressed by isatin administration, indicating that the inhibition of oxidative deamination effectively suppressed superoxide production. These data suggest that the exacerbation effect of isatin is associated, at least in part, with increased norepinephrine levels but not with superoxide production. To the best of our knowledge, this is the first report of isatin involvement in the pathogenesis and/or development of acute kidney injury.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/etiologia , Inibidores da Monoaminoxidase/farmacologia , Traumatismo por Reperfusão/complicações , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Animais , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Inibidores da Monoaminoxidase/uso terapêutico , Norepinefrina/sangue , Ratos , Ratos Sprague-Dawley , Superóxidos/metabolismo
7.
Eur J Pharmacol ; 781: 36-44, 2016 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-27041645

RESUMO

Excitation of renal sympathetic nervous activity and the resulting increased levels of renal venous norepinephrine play important roles in renal ischaemia/reperfusion injury in rats. This study examined the effects of yohimbine, a non-selective α2-adrenoceptor antagonist, on renal venous norepinephrine levels and kidney function in acute kidney injury. Acute ischaemia/reperfusion-induced kidney injury was induced in rats by clamping the left renal artery and vein for 45min, followed by reperfusion, 2 weeks after a contralateral nephrectomy. Intravenous injection of yohimbine (0.1mg/kg) 5min prior to ischaemia significantly attenuated kidney injury and decreased the renal venous norepinephrine levels, as compared with vehicle-treated rats. To investigate the involvement of α2-adrenoceptor subtypes, we pre-treated with JP-1302, a selective α2C-adrenoceptor antagonist (1mg/kg). This suppressed renal venous norepinephrine levels and tumour necrosis factor-α and monocyte chemoattractant protein-1 mRNA levels after reperfusion and improved kidney function. Pre-treatment with BRL44408, a selective α2A-adrenoceptor antagonist (1mg/kg), or imiloxan, a selective α2B-adrenoceptor antagonist (1mg/kg) had no effect on renal function or tissue injury. These results suggest that yohimbine prevented ischaemia/reperfusion-induced kidney injury by inhibiting α2C-adrenoceptors and suppressing pro-inflammatory cytokine expression.


Assuntos
Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Citoproteção/efeitos dos fármacos , Rim/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/metabolismo , Traumatismo por Reperfusão/complicações , Ioimbina/farmacologia , Acridinas/farmacologia , Injúria Renal Aguda/sangue , Injúria Renal Aguda/etiologia , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Quimiocina CCL2/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Norepinefrina/metabolismo , Piperazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
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