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1.
Ther Apher Dial ; 2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32524727

RESUMO

A novel approach is required for standard therapy-resistant peripheral arterial disease (PAD). This is a single-center, single-arm, interventional study (LDL Apheresis-Mediated Endothelial Activation Therapy to Severe-Peripheral Artery Disease study), which aims to evaluate the efficacy and safety of lipoprotein apheresis (LA) with a dextran sulfate cellulose column in PAD with controlled serum cholesterol levels. The study participants have standard therapy-resistant PAD with controlled serum cholesterol levels. A total of 35 patients undergo 10 sessions of LA therapy. The ankle-brachial index and vascular quality of life questionnaire are assessed before and after the treatment period as primary outcomes. Registration of patients began in November 2015 and is planned to be concluded in October 2020.

2.
Curr Hypertens Rep ; 22(3): 22, 2020 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-32114685

RESUMO

PURPOSE OF REVIEW: The renin-angiotensin-aldosterone system (RAAS) plays important roles in regulating blood pressure and body fluid, which contributes to the pathophysiology of hypertension and cardiovascular/renal diseases. However, accumulating evidence has further revealed the complexity of this signal transduction system, including direct interactions with other receptors and proteins. This review focuses on recent research advances in RAAS with an emphasis on its receptors. RECENT FINDINGS: Both systemically and locally produced angiotensin II (Ang II) bind to Ang II type 1 receptor (AT1R) and elicit strong biological functions. Recent studies have shown that Ang II-induced activation of Ang II type 2 receptor (AT2R) elicits the opposite functions to those of AT1R. However, accumulating evidence has now expanded the components of RAAS, including (pro)renin receptor, angiotensin-converting enzyme 2, angiotensin 1-7, and Mas receptor. In addition, the signal transductions of AT1R and AT2R are regulated by not only Ang II but also its receptor-associated proteins such as AT1R-associated protein and AT2R-interacting protein. Recent studies have indicated that inappropriate activation of local mineralocorticoid receptor contributes to cardiovascular and renal tissue injuries through aldosterone-dependent and -independent mechanisms. Since the mechanisms of RAAS signal transduction still remain to be elucidated, further investigations are necessary to explore novel molecular mechanisms of the RAAS, which will provide alternative therapeutic agents other than existing RAAS blockers.

3.
Sci Rep ; 10(1): 1782, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024850

RESUMO

Chronic kidney disease (CKD) progresses to end-stage renal failure via renal tubulointerstitial fibrosis. Malnutrition, inflammation, and arteriosclerosis interact to exacerbate the poor prognosis of CKD, and their effective management is thus essential. The traditional Japanese medicine Rikkunshito (RKT) exerts appetite-stimulating effects via ghrelin, which attenuates inflammation and fibrosis. We evaluated the therapeutic effect of RKT in unilateral ureter obstruction (UUO)-induced renal fibrosis/inflammation and body weight loss in mice. UUO and sham-operated mice were fed a standard diet or diet containing 3.0% RKT. Renal fibrosis was investigated by histopathology and macrophage infiltration was determined by immunohistochemistry. Expression levels of genes associated with fibrosis, inflammation, ghrelin, and mitochondrial function were determined by quantitative reverse transcription-polymerase chain reaction and western blot analyses. RKT treatment partially prevented UUO-induced weight loss but failed to attenuate renal fibrosis and inflammation. Renal expression of sirtuin 1, a ghrelin-downstream signalling molecule, and gene expression of peroxisome proliferator-activated receptor-γ coactivator 1α and Bcl-2/adenovirus E1B interacting protein 3 were unaffected by RKT. These results indicate that RKT inhibits weight loss but does not improve renal fibrosis or inflammation in a rapidly progressive renal fibrosis mouse model. RKT may have a protective effect on weight loss associated with CKD.

5.
Sci Rep ; 9(1): 16550, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31719572

RESUMO

The proximal tubule is a particularly important site for ageing-related kidney damage. Sirtuin 1 (SIRT1), an NAD+ (nicotinamide adenine dinucleotide)-dependent deacetylase in the proximal tubule, may be involved in renal injury associated with ageing. However, the mechanisms of SIRT1 regulation remain to be elucidated. We recently reported that angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP)-deficient mice displayed age-associated renal function decline and tubulointerstitial fibrosis. Our data showed that SIRT1 protein expression was reduced in ATRAP-deficient mice, although the relationship between ATRAP deficiency and age-associated renal fibrosis is still not fully understood. It is, therefore, necessary to investigate how ATRAP affects SIRT1 protein expression to resolve ageing-associated kidney dysfunction. Here, since ageing studies are inherently lengthy, we used an ex vivo model of the proximal tubule to determine the role of ATRAP in SIRT1 protein expression. We first generated a clonal immortalised human renal proximal tubule epithelial cell line (ciRPTEC) expressing AT1R and ATRAP. Using this cell line, we demonstrated that ATRAP knockdown reduced SIRT1 protein expression in the ciRPTEC but did not alter SIRT1 mRNA expression. Thus, ATRAP likely mediates SIRT1 protein abundance in ciRPTEC.

6.
Int J Cardiol Heart Vasc ; 25: 100422, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31517037

RESUMO

Background: Both native T1 time and extracellular volume (ECV) fraction have been shown to be important measures for the detection of myocardial fibrosis. However, ECV determination requires the administration of an intravenous contrast agent, whereas native T1 mapping can be performed without a contrast agent. Methods: Here, we conducted a meta-analysis of myocardial native T1 data obtained for non-ischemic cardiomyopathy (NIC) patients and controls. A literature review included studies that applied T1 mapping using modified Look-Locker inversion recovery to measure myocardial fibrosis, and the results were validated by comparing datasets for dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM) patients and healthy controls (HCs). Results: We identified 16 eligible studies. Pooled mean differences (MDs) and 95% confidence intervals (CIs) were estimated as follows. Native T1 at 1.5-T, DCM vs. HC: MD = 45.26 (95% CI: 30.92-59.59); HCM vs. HC: MD = 47.09 (95% CI: 32.42-61.76). Native T1 at 3.0-T, DCM vs. HC: MD = 82.52 (95% CI: 47.60-117.44); HCM vs. HC: MD = 115.87 (95% CI: 50.71-181.04). ECV at 1.5-T, DCM vs. HC: MD = 4.26 (95% CI: 3.06-5.46); HCM vs. HC: MD = 1.49 (95% CI: -1.45-4.43). ECV at 3.0-T, DCM vs. HC: MD = 8.40 (95% CI: 2.94-13.86); HCM vs. HC: MD = 8.02 (95% CI: 5.45-1-0.59). Conclusion: In conclusion, native T1 values were significantly different between NIC patients and controls. Native T1 mapping may be a useful noninvasive method to detect diffuse myocardial fibrosis in NIC patients.

7.
Cardiovasc Diabetol ; 18(1): 110, 2019 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-31455298

RESUMO

BACKGROUND: The Y-AIDA study was designed to investigate the renal- and home blood pressure (BP)-modulating effects of add-on dapagliflozin treatment in Japanese individuals with type 2 diabetes mellitus (T2DM) and albuminuria. METHODS: We conducted a prospective, multicenter, single-arm study. Eighty-six patients with T2DM, HbA1c 7.0-10.0%, estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m2, and urine albumin-to-creatinine ratio (UACR) ≥ 30 mg/g creatinine (gCr) were enrolled, and 85 of these patients were administered add-on dapagliflozin for 24 weeks. The primary and key secondary endpoints were change from baseline in the natural logarithm of UACR over 24 weeks and change in home BP profile at week 24. RESULTS: Baseline median UACR was 181.5 mg/gCr (interquartile range 47.85, 638.0). Baseline morning, evening, and nocturnal home systolic/diastolic BP was 137.6/82.7 mmHg, 136.1/79.3 mmHg, and 125.4/74.1 mmHg, respectively. After 24 weeks, the logarithm of UACR decreased by 0.37 ± 0.73 (P < 0.001). In addition, changes in morning, evening, and nocturnal home BP from baseline were as follows: morning systolic/diastolic BP - 8.32 ± 11.42/- 4.18 ± 5.91 mmHg (both P < 0.001), evening systolic/diastolic BP - 9.57 ± 12.08/- 4.48 ± 6.45 mmHg (both P < 0.001), and nocturnal systolic/diastolic BP - 2.38 ± 7.82/- 1.17 ± 5.39 mmHg (P = 0.0079 for systolic BP, P = 0.0415 for diastolic BP). Furthermore, the reduction in UACR after 24 weeks significantly correlated with an improvement in home BP profile, but not with changes in other variables, including office BP. Multivariate linear regression analysis also revealed that the change in morning home systolic BP was a significant contributor to the change in log-UACR. CONCLUSIONS: In Japanese patients with T2DM and diabetic nephropathy, dapagliflozin significantly improved albuminuria levels and the home BP profile. Improved morning home systolic BP was associated with albuminuria reduction. Trial registration The study is registered at the UMIN Clinical Trials Registry (UMIN000018930; http://www.umin.ac.jp/ctr/index-j.htm ). The study was conducted from July 1, 2015 to August 1, 2018.


Assuntos
Albuminúria/tratamento farmacológico , Compostos Benzidrílicos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Glucosídeos/uso terapêutico , Rim/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Adulto , Idoso , Albuminúria/diagnóstico , Albuminúria/epidemiologia , Albuminúria/fisiopatologia , Compostos Benzidrílicos/efeitos adversos , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Monitorização Ambulatorial da Pressão Arterial , Ritmo Circadiano , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/fisiopatologia , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Glucosídeos/efeitos adversos , Hemoglobina A Glicada/metabolismo , Humanos , Japão/epidemiologia , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
8.
J Am Heart Assoc ; 8(8): e012395, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30977419

RESUMO

Background We have previously shown that ATRAP (angiotensin II receptor-associated protein; Agtrap) interacts with AT1R (angiotensin II type 1 receptor) and promotes constitutive internalization of AT 1R so as to inhibit hyperactivation of its downstream signaling. In response to angiotensin II , systemic ATRAP deficiency exacerbates angiotensin II -mediated hypertension via hyperactivation of renal tubular AT 1R. Although ATRAP expression is abundant in renal proximal tubules, little is known about the actual function of renal proximal tubule ATRAP in angiotensin-mediated hypertension. Methods and Results In this study, we examined the in vivo functional role of renal proximal tubule ATRAP in angiotensin-dependent hypertension. We succeeded in generating proximal tubule-specific ATRAP knockout ( PT - KO ) mice for the first time using the Cre/loxP system with Pepck-Cre. Detailed analysis of renal ATRAP expression in PT - KO mice estimated by immunohistochemical and laser-capture microdissection analysis revealed that ATRAP mRNA expression decreased by ≈80% in proximal regions of the nephron in PT - KO mice compared with wild-type ( WT ) mice. We compared blood pressure of PT - KO and WT mice using both tail-cuff and radiotelemetric methods. Blood pressure of PT - KO mice was comparable with that of WT mice at baseline. Moreover, no significant differences were noted in pressor response to angiotensin II (600 ng/kg per min or 1000 ng/kg per minute) infusion between PT - KO and WT mice. In addition, angiotensin II -mediated cardiac hypertrophy was identical between PT - KO and WT mice. Conclusions ATRAP deficiency in proximal tubules did not exacerbate angiotensin-dependent hypertension in vivo. The results indicate that renal proximal tubule ATRAP has a minor role in angiotensin-dependent hypertension in vivo.

9.
Sci Rep ; 9(1): 6201, 2019 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-30996242

RESUMO

The underlying pathogenesis of chronic kidney disease involves an activated renin-angiotensin system and systemic inflammation which ultimately develop renal injury. Rikkunshito (RKT) has been reported to exert anti-fibrotic and anti-inflammatory effects through enhancement of ghrelin signaling pathway. In this study, we investigated the effects of RKT on renal fibrosis and inflammation in angiotensin II (Ang II)-induced renal injury model. Ang II-infused mice exhibited hypertension, cardiac hypertrophy, increases in blood urea nitrogen and serum creatinine, moderate albuminuria and renal pathological changes such as mild urinary cast, interstitial macrophage infiltration and modest interstitial fibrosis. RKT had no evident effects on the Ang II-induced renal functional insufficiency and fibrosis, but attenuated renal interstitial macrophage infiltration. In addition, RKT significantly restored the Ang II-induced alteration in the expression of renal fibrosis- and inflammation-related genes such as type 3 collagen, transforming growth factor-ß, monocyte chemoattractant protein-1 and interleukin-6. Furthermore, although RKT did not affect the expression of renal ghrelin receptor, an Ang II-induced decrease in renal sirtuin 1 expression, a critical down-stream pathway of the ghrelin receptor, was restored by RKT. These findings suggest that RKT potentially has a renal anti-inflammatory effect in the development of renal injury, and this effect could be mediated by the ghrelin signaling pathway.

10.
Biomed Res Int ; 2018: 2817045, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30515388

RESUMO

Abnormal angiogenesis plays a major role in the development of early stage diabetic nephropathy. Vascular endothelial growth factor (VEGF) is a classical proangiogenic factor that regulates abnormal glomerular angiogenesis linked to glomerular hypertrophy in the early stage of diabetic nephropathy. Leucine-rich α-2-glycoprotein-1 (LRG1) was recently reported as a novel proangiogenic factor that is expressed in endothelial cells and promotes angiogenesis by modulating the transforming growth factor-ß signaling pathway. However, the pathophysiology of LRG1 in diabetic nephropathy remains largely unknown. In the present study, we investigated intrarenal expression of the novel proangiogenic factor LRG1 in diabetic db/db mice by immunohistochemistry and a laser capture microdissection method during the development of diabetic nephropathy. We hypothesized that glomerular LRG1 expression is increased earlier than VEGF expression under conditions of pathological angiogenesis in the early stage of diabetic nephropathy. Thus, we compared glomerular expression of VEGF and LRG1 in diabetic db/db mice at 16 and 24 weeks of age. At 16 weeks, diabetic db/db mice exhibited glomerular hypertrophy with abnormal angiogenesis characterized by endothelial cell proliferation, which was concomitant with an increase in LRG1 expression of glomerular endothelial cells. However, glomerular VEGF expression was not increased at this early stage. At 24 weeks, the features of early diabetic nephropathy in db/db mice had developed further, along with further enhanced glomerular LRG1 expression. At this late stage, glomerular VEGF and fibrosis-related-gene expression was also significantly increased compared with nondiabetic db/m mice. These results suggest that LRG1 plays a pivotal role in the initial development of diabetic nephropathy by promoting abnormal angiogenesis, thereby suggesting that LRG1 is a potential preemptive therapeutic target of diabetic nephropathy.


Assuntos
Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Glicoproteínas/genética , Fator A de Crescimento do Endotélio Vascular/genética , Animais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Camundongos , Camundongos Endogâmicos NOD , Neovascularização Patológica/genética
11.
Diabetes ; 67(10): 2096-2106, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30065034

RESUMO

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease worldwide, but its molecular pathogenesis is not well defined, and there are no specific treatments. In humans, there is a strong genetic component determining susceptibility to DN. However, specific genes controlling DN susceptibility in humans have not been identified. In this study, we describe a mouse model combining type 1 diabetes with activation of the renin-angiotensin system (RAS), which develops robust kidney disease with features resembling human DN: heavy albuminuria, hypertension, and glomerulosclerosis. Additionally, there is a powerful effect of genetic background regulating susceptibility to nephropathy; the 129 strain is susceptible to kidney disease, whereas the C57BL/6 strain is resistant. To examine the molecular basis of this differential susceptibility, we analyzed the glomerular transcriptome of young mice early in the course of their disease. We find dramatic differences in regulation of immune and inflammatory pathways, with upregulation of proinflammatory pathways in the susceptible (129) strain and coordinate downregulation in the resistant (C57BL/6) strain. Many of these pathways are also upregulated in rat models and in humans with DN. Our studies suggest that genes controlling inflammatory responses, triggered by hyperglycemia and RAS activation, may be critical early determinants of susceptibility to DN.


Assuntos
Nefropatias Diabéticas/genética , Nefropatias Diabéticas/imunologia , Inflamação/genética , Inflamação/imunologia , Nefropatias/genética , Nefropatias/imunologia , Animais , Glicemia/genética , Glicemia/imunologia , Western Blotting , Predisposição Genética para Doença/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real
13.
Sci Rep ; 8(1): 2846, 2018 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-29434287

RESUMO

Enhancement of AT1 receptor-associated protein (ATRAP) in adipose tissue improves high fat diet (HFD)-induced visceral obesity and insulin resistance, and suppresses adipose oxidative stress. However, HFD loading is not a direct stimulatory factor for AT1 receptor. In the present study, we investigated the effect of chronic, low-dose angiotensin II (Ang II) stimulation on glucose and lipid metabolism in mice and functional role of ATRAP. ATRAP expression was higher in adipose tissue (5-10-fold) and skeletal muscle tissue (approximately 1.6-fold) in ATRAP transgenic (TG) mice compared with wild-type (WT) mice. After Ang II infusion, insulin sensitivity was impaired in WT mice, but this response was suppressed in TG mice. Unexpectedly, Ang II infusion did not affect the adipose tissue profile in WT or TG mice. However, in skeletal muscle tissue, Ang II stimulus caused an increase in oxidative stress and activation of p38 MAPK, resulting in a decrease in glucose transporter type 4 expression in WT mice. These responses were suppressed in TG mice. Our study suggests that Ang II-induced insulin resistance is suppressed by increased ATRAP expression in skeletal muscle tissue. Hyperactivity of AT1 receptor could be related to formation of insulin resistance related to metabolic syndrome.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Angiotensina II/administração & dosagem , Resistência à Insulina , Músculo Esquelético/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Angiotensina II/farmacologia , Animais , Glucose/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Infusões Intravenosas , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos , Músculo Esquelético/efeitos dos fármacos , Estresse Oxidativo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
14.
Atherosclerosis ; 269: 236-244, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29407599

RESUMO

BACKGROUND AND AIMS: The components of the renin-angiotensin system in leukocytes is involved in the pathophysiology of non-communicable diseases (NCDs), including hypertension, atherosclerosis and chronic kidney disease. Angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP) is an AT1R-specific binding protein, and is able to inhibit the pathological activation of AT1R signaling in certain animal models of NCDs. The aim of the present study was to investigate the expression and regulation of ATRAP in leukocytes. METHODS: Human leukocyte ATRAP mRNA was measured with droplet digital polymerase chain reaction system, and analyzed in relation to the clinical variables. We also examined the leukocyte cytokines mRNA in bone-marrow ATRAP-deficient and wild-type chimeric mice after injection of low-dose lipopolysaccharide. RESULTS: The ATRAP mRNA was abundantly expressed in leukocytes, predominantly granulocytes and monocytes, of healthy subjects. In 86 outpatients with NCDs, leukocyte ATRAP mRNA levels correlated positively with granulocyte and monocyte counts and serum C-reactive protein levels. These positive relationships remained significant even after adjustment. Furthermore, the leukocyte ATRAP mRNA was significantly associated with the interleukin-1ß, tumor necrosis factor-α and monocyte chemotactic protein-1 mRNA levels in leukocytes of NCDs patients. In addition, the leukocyte interleukin-1ß mRNA level was significantly upregulated in bone marrow ATRAP-deficient chimeric mice in comparison to wild-type chimeric mice after injection of lipopolysaccharide. CONCLUSIONS: These results suggest that leukocyte ATRAP is an emerging marker capable of reflecting the systemic and leukocyte inflammatory profile, and plays a role as an anti-inflammatory factor in the pathophysiology of NCDs.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Inflamação/metabolismo , Leucócitos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Adaptadoras de Transdução de Sinal/genética , Idoso , Idoso de 80 Anos ou mais , Animais , Estudos de Casos e Controles , Citocinas/genética , Modelos Animais de Doenças , Feminino , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/imunologia , Leucócitos/imunologia , Lipopolissacarídeos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Doenças não Transmissíveis
15.
Nat Rev Nephrol ; 14(1): 48-56, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29062142

RESUMO

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease in the developed world. Accordingly, an urgent need exists for new, curative treatments as well as for biomarkers to stratify risk of DN among individuals with diabetes mellitus. A barrier to progress in these areas has been a lack of animal models that faithfully replicate the main features of human DN. Such models could be used to define the pathogenesis, identify drug targets and test new therapies. Owing to their tractability for genetic manipulation, mice are widely used to model human diseases, including DN. Questions have been raised, however, about the general utility of mouse models in human drug discovery. Standard mouse models of diabetes typically manifest only modest kidney abnormalities, whereas accelerated models, induced by superimposing genetic stressors, recapitulate key features of human DN. Incorporation of systems biology approaches and emerging data from genomics and metabolomics studies should enable further model refinement. Here, we discuss the current status of mouse models for DN, their limitations and opportunities for improvement. We emphasize that future efforts should focus on generating robust models that reproduce the major clinical and molecular phenotypes of human DN.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Modelos Animais de Doenças , Falência Renal Crônica , Camundongos , Animais , Análise de Sistemas , Biologia de Sistemas
17.
J Am Heart Assoc ; 6(8)2017 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-28751545

RESUMO

BACKGROUND: The kidney is easily affected by aging-associated changes, including glomerulosclerosis, tubular atrophy, and interstitial fibrosis. Particularly, renal tubulointerstitial fibrosis is a final common pathway in most forms of progressive renal disease. Angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP), which was originally identified as a molecule that binds to AT1R, is highly expressed in the kidney. Previously, we have shown that ATRAP suppresses hyperactivation of AT1R signaling, but does not affect physiological AT1R signaling. METHODS AND RESULTS: We hypothesized that ATRAP has a novel functional role in the physiological age-degenerative process, independent of modulation of AT1R signaling. ATRAP-knockout mice were used to study the functional involvement of ATRAP in the aging. ATRAP-knockout mice exhibit a normal age-associated appearance without any evident alterations in physiological parameters, including blood pressure and cardiovascular and metabolic phenotypes. However, in ATRAP-knockout mice compared with wild-type mice, the following takes place: (1) age-associated renal function decline and tubulointerstitial fibrosis are more enhanced; (2) renal tubular mitochondrial abnormalities and subsequent increases in the production of reactive oxygen species are more advanced; and (3) life span is 18.4% shorter (median life span, 100.4 versus 123.1 weeks). As a key mechanism, age-related pathological changes in the kidney of ATRAP-knockout mice correlated with decreased expression of the prosurvival gene, Sirtuin1. On the other hand, chronic angiotensin II infusion did not affect renal sirtuin1 expression in wild-type mice. CONCLUSIONS: These results indicate that ATRAP plays an important role in inhibiting kidney aging, possibly through sirtuin1-mediated mechanism independent of blocking AT1R signaling, and further protecting normal life span.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Angiotensina II/metabolismo , Rim/metabolismo , Longevidade , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Adaptadoras de Transdução de Sinal/genética , Fatores Etários , Angiotensina II/administração & dosagem , Animais , Colágeno/genética , Colágeno/metabolismo , Fibrose , Genótipo , Rim/fisiopatologia , Rim/ultraestrutura , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Estresse Oxidativo , Fenótipo , Espécies Reativas de Oxigênio/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Transdução de Sinais , Sirtuína 1/genética , Sirtuína 1/metabolismo , Fatores de Tempo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
18.
Physiol Rep ; 5(11)2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28611155

RESUMO

Plasma membrane calcium pump isoform 1 (PMCA1) is encoded by ATPase plasma membrane Ca2+transporting 1 (ATP2B1), the most likely candidate gene responsible for hypertension. Although PMCA1 is highly expressed in the kidney, little is known about regulation of its renal expression in various pathological conditions in vivo. Our study was designed to elucidate regulation of renal PMCA1 expression in mice. We employed three mouse models for kidney disease. These were the unilateral ureteral obstruction (UUO), the remnant kidney using 5/6 nephrectomy, and chronic angiotensin II administration models. Mice were assessed for systolic blood pressure and renal injury in accordance with the damage induced in the specific model. Kidney PMCA1 mRNA levels were measured in all mice. The UUO model showed renal fibrosis but no changes in blood pressure or renal PMCA1 mRNA expression. Similarly, the 5/6 nephrectomy model exhibited declined renal function without changes in blood pressure or renal PMCA1 mRNA expression. In contrast, chronic angiotensin II administration increased albuminuria and blood pressure as well as significantly increasing renal PMCA1 mRNA and protein expression. These results suggest that renal PMCA1 has a role as one of the molecules involved in angiotensin II-induced hypertension and kidney injury.


Assuntos
Angiotensina II/metabolismo , Regulação da Expressão Gênica/fisiologia , Hipertensão/metabolismo , ATPases Transportadoras de Cálcio da Membrana Plasmática/biossíntese , Angiotensina II/toxicidade , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Hipertensão/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nefrectomia , Obstrução Ureteral/metabolismo
19.
Int J Mol Sci ; 18(6)2017 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-28604611

RESUMO

The epithelial sodium channel (ENaC) plays critical roles in maintaining fluid and electrolyte homeostasis and is located in the aldosterone-sensitive distal nephron (ASDN). We previously found that Nedd4-2 C2 knockout (KO) mice showed salt-sensitive hypertension with paradoxically enhanced ENaC gene expression in ASDN under high oral salt intake. Eplerenone (EPL), a selective aldosterone blocker, is a promising therapeutic option for resistant or/and salt-sensitive hypertension. We examined the effect of EPL on Nedd4-2 C2 KO mice with respect to blood pressure, metabolic parameters, and molecular level changes in ASDN under high oral salt intake. We found that EPL failed to reduce blood pressure in KO mice with high oral salt intake and upregulated ENaC expression in ASDN. Thus, salt-sensitive hypertension in Nedd4-2 C2 KO was EPL-resistant. Gene expression analyses of laser-captured specimens in ASDN suggested the presence of non-aldosterone-dependent activation of ENaC transcription in ASDN of Nedd4-2 C2 KO mice, which was abolished by amiloride treatment. Our results from Nedd4-2 C2 KO mice suggest that enhanced ENaC gene expression is critically involved in salt-sensitive hypertension under certain conditions of specific enzyme isoforms for their ubiquitination.


Assuntos
Canais Epiteliais de Sódio/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Ubiquitina-Proteína Ligases Nedd4/genética , Espironolactona/análogos & derivados , Animais , Pressão Sanguínea/efeitos dos fármacos , Canais Epiteliais de Sódio/genética , Eplerenona , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Hipertensão/metabolismo , Masculino , Camundongos , Camundongos Knockout , Cloreto de Sódio na Dieta/farmacologia , Espironolactona/farmacologia
20.
Clin Exp Hypertens ; 39(7): 665-671, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28635327

RESUMO

As there may be an association between within-visit blood pressure (BP) variability and cardiovascular disease (CVD), we investigated the clinical significance of this BP variability in non-dialysis chronic kidney disease (CKD) patients. MATERIALS AND METHODS: According to the median of coefficient of variation (CV) of three systolic BP (SBP) readings within a single visit, we divided hypertensive patients with stage G1-4 CKD already treated with antihypertensive therapy into the high SBP-CV group and the low SBP-CV group. Univariate and multivariate linear regression analyses were also performed to explore the contributing factors to within-visit BP variability. RESULTS: In the high SBP-CV group, the clinic BP, total cholesterol level, dyslipidemia, and past history of CVD were significantly greater, while α1-blockers and renin-angiotensin system (RAS) inhibitors usage were significantly reduced compared with the lower SBP-CV group. Within-visit BP variability was significantly and positively correlated with total cholesterol (R = 0.392, P < 0.001) and low-density lipoprotein cholesterol (R = 0.284, P = 0.013). Total cholesterol (ß = 0.269, P = 0.024), α1-blockers usage (ß = -0.260, P = 0.015), and RAS inhibitors usage (ß = -0.266, P = 0.017) were shown to independently contribute to the within-visit BP variability after adjustment for age, sex, presence of diabetes, CVD history, statins usage, and clinic SBP. CONCLUSIONS: We show that within-visit BP variability may be a clinically relevant factor of CVD risk, and lipid lowering and/or anti-hypertensive therapies using RAS inhibitors and α1-blockers may be associated with the improved within-visit BP variability observed in non-dialysis CKD patients.


Assuntos
Pressão Sanguínea/fisiologia , Doenças Cardiovasculares/etiologia , Hipertensão/fisiopatologia , Insuficiência Renal Crônica/fisiopatologia , Idoso , Anti-Hipertensivos/uso terapêutico , Determinação da Pressão Arterial , Doenças Cardiovasculares/tratamento farmacológico , Feminino , Humanos , Hipertensão/complicações , Lipoproteínas LDL/metabolismo , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/complicações , Sistema Renina-Angiotensina/fisiologia , Fatores de Risco
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