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1.
Nihon Rinsho ; 73(11): 1876-84, 2015 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-26619662

RESUMO

For clinical practice guidelines for the management of hypertension with CKD, the Japanese Society of Nephrology (JSN) and the Japanese Society of Hypertension (JSH) evaluated recently published evidence in corporation with each other. After considerable and careful discussion, both JSN and JSH revised their respective guidelines [the Evidence-based Clinical Practice Guideline for CKD 2013 (JSN-CKD GL 2013) and JSH2014]. This section will mainly introduce anti-hypertensive therapy recommended for the management of hypertension with CKD in both guidelines. Recommendation statements for the Management of Hypertension with CKD are as follows: 1) Anti-hypertensive therapy in CKD is strongly recommended to inhibit or prevent the progression of renal dysfunction and to prevent the occurrence or recurrence of CVD by reducing blood pressure (BP) (Grade A). 2) In all diabetic CKD, the target level of clinic BP is recommended as < 130/80 mmHg, irrespective of the presence or absence of albuminuria/proteinuria (Grade B). 3) In all non-diabetic CKD, the target level of clinic BP is strongly recommended as consistently < 140/90 mmHg, irrespective of the presence or absence of albuminuria/proteinuria (Grade A). 4) In non-diabetic CKD with A2 and A3 categories, the target level of clinic BP can be set as < 130/80 mmHg (Grade C1). 5) In diabetic CKD with A1 category, ARBs and ACE inhibitors are suggested as first-line anti-hypertensive drugs(Grade C1). 6) In diabetic CKD with A2 and A3 categories, ARBs and ACE inhibitors are recommended as first-line anti-hypertensive drugs (Grade A). 7) In non-diabetic CKD with A1 category, ARBs, ACE inhibitors, calcium channel blockers (CCBs) and diuretics are recommended as first-line anti-hypertensive drugs (Grade B). 8) In non-diabetic CKD with A2 and A3 categories, ARBs and ACE inhibitors are recommended as first-line anti-hypertensive drugs (Grade B).


Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Guias de Prática Clínica como Assunto , Insuficiência Renal Crônica/complicações , Complicações do Diabetes , Humanos , Hipertensão/complicações , Proteinúria
2.
Clin Exp Hypertens ; 36(4): 244-50, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-23848219

RESUMO

Diuretics or calcium channel blockers (CCBs) are used concomitantly with an angiotensin II receptor blocker (ARB). However, it is not established which ARB-based combination therapy is the most effective and safe. This prospective randomized open-label study compared the efficacy and safety of a fixed-dose tablet of losartan (LST)-hydrochlorothiazide (HCTZ) (n = 99) and LST-amlodipine (AML) (n = 77) in Japanese patients whose hypertension was uncontrolled by ARB monotherapy. Blood pressure changed similarly over the 12-month study period. Only LST-HCTZ significantly increased serum uric acid (SUA) in patients with low baseline SUA (<5.6 mg/dL) but not in patients with high baseline SUA.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/administração & dosagem , Diuréticos/administração & dosagem , Hipertensão/tratamento farmacológico , Adulto , Idoso , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Hidroclorotiazida/administração & dosagem , Hipertensão/sangue , Hipertensão/fisiopatologia , Losartan/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento , Ácido Úrico/sangue , Adulto Jovem
3.
Perit Dial Int ; 43(6): 457-466, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37632293

RESUMO

BACKGROUND: This multi-institutional, observational study examined whether the outcomes after peritoneal dialysis (PD) catheter placement in Japan meet the audit criteria of the International Society for Peritoneal Dialysis (ISPD) guideline and identified factors affecting technique survival and perioperative complications. METHODS: Adult patients who underwent first PD catheter placement for end-stage kidney disease between April 2019 and March 2021 were followed until PD withdrawal, kidney transplantation, transfer to other facilities, death, 1 year after PD start or March 2022, whichever came first. Primary outcomes were time to catheter patency failure and technique failure, and perioperative infectious complications within 30 days of catheter placement. Secondary outcomes were perioperative complications. Appropriate statistical analyses were performed to identify factors associated with the outcomes of interest. RESULTS: Of the total 409 patients, 8 who underwent the embedded catheter technique did not have externalised catheters. Of the 401 remaining patients, catheter patency failure occurred in 25 (6.2%). Technical failure at 12 months after PD catheter placement calculated from cumulative incidence function was 15.3%. On Cox proportional hazards model analysis, serum albumin (hazard ratio (HR) 0.44; 95% confidence interval (CI) 0.27-0.70) and straight type catheter (HR 2.14; 95% CI 1.24-3.69) were the independent risk factors for technique failure. On logistic regression analysis, diabetes mellitus was the only independent risk factor for perioperative infectious complications (odds ratio 2.70, 95% CI 1.30-5.58). The occurrence rate of perioperative complications generally met the audit criteria of the ISPD guidelines. CONCLUSION: PD catheter placement in Japan was proven to be safe and appropriate.


Assuntos
Falência Renal Crônica , Diálise Peritoneal , Adulto , Humanos , Diálise Peritoneal/efeitos adversos , Diálise Peritoneal/métodos , Cateteres de Demora/efeitos adversos , Japão , Cateterismo/métodos , Peritônio , Falência Renal Crônica/terapia , Falência Renal Crônica/etiologia
4.
Am J Physiol Heart Circ Physiol ; 302(3): H724-32, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22101521

RESUMO

p66Shc, a longevity adaptor protein, is demonstrated as a key regulator of reactive oxygen species (ROS) metabolism involved in aging and cardiovascular diseases. Vascular endothelial growth factor (VEGF) stimulates endothelial cell (EC) migration and proliferation primarily through the VEGF receptor-2 (VEGFR2). We have shown that ROS derived from Rac1-dependent NADPH oxidase are involved in VEGFR2 autophosphorylation and angiogenic-related responses in ECs. However, a role of p66Shc in VEGF signaling and physiological responses in ECs is unknown. Here we show that VEGF promotes p66Shc phosphorylation at Ser36 through the JNK/ERK or PKC pathway as well as Rac1 binding to a nonphosphorylated form of p66Shc in ECs. Depletion of endogenous p66Shc with short interfering RNA inhibits VEGF-induced Rac1 activity and ROS production. Fractionation of caveolin-enriched lipid raft demonstrates that p66Shc plays a critical role in VEGFR2 phosphorylation in caveolae/lipid rafts as well as downstream p38MAP kinase activation. This in turn stimulates VEGF-induced EC migration, proliferation, and capillary-like tube formation. These studies uncover a novel role of p66Shc as a positive regulator for ROS-dependent VEGFR2 signaling linked to angiogenesis in ECs and suggest p66Shc as a potential therapeutic target for various angiogenesis-dependent diseases.


Assuntos
Células Endoteliais/enzimologia , Sistema de Sinalização das MAP Quinases/fisiologia , Neovascularização Fisiológica/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Proteínas Adaptadoras da Sinalização Shc/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Cavéolas/enzimologia , Células Endoteliais/citologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Microdomínios da Membrana/enzimologia , Fosforilação/efeitos dos fármacos , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo
5.
Circ Res ; 107(6): 787-99, 2010 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-20671235

RESUMO

RATIONALE: Copper, an essential nutrient, has been implicated in vascular remodeling and atherosclerosis with unknown mechanism. Bioavailability of intracellular copper is regulated not only by the copper importer CTR1 (copper transporter 1) but also by the copper exporter ATP7A (Menkes ATPase), whose function is achieved through copper-dependent translocation from trans-Golgi network (TGN). Platelet-derived growth factor (PDGF) promotes vascular smooth muscle cell (VSMC) migration, a key component of neointimal formation. OBJECTIVE: To determine the role of copper transporter ATP7A in PDGF-induced VSMC migration. METHODS AND RESULTS: Depletion of ATP7A inhibited VSMC migration in response to PDGF or wound scratch in a CTR1/copper-dependent manner. PDGF stimulation promoted ATP7A translocation from the TGN to lipid rafts, which localized at the leading edge, where it colocalized with PDGF receptor and Rac1, in migrating VSMCs. Mechanistically, ATP7A small interfering RNA or CTR small interfering RNA prevented PDGF-induced Rac1 translocation to the leading edge, thereby inhibiting lamellipodia formation. In addition, ATP7A depletion prevented a PDGF-induced decrease in copper level and secretory copper enzyme precursor prolysyl oxidase (Pro-LOX) in lipid raft fraction, as well as PDGF-induced increase in LOX activity. In vivo, ATP7A expression was markedly increased and copper accumulation was observed by synchrotron-based x-ray fluorescence microscopy at neointimal VSMCs in wire injury model. CONCLUSIONS: These findings suggest that ATP7A plays an important role in copper-dependent PDGF-stimulated VSMC migration via recruiting Rac1 to lipid rafts at the leading edge, as well as regulating LOX activity. This may contribute to neointimal formation after vascular injury. Our findings provide insight into ATP7A as a novel therapeutic target for vascular remodeling and atherosclerosis.


Assuntos
Adenosina Trifosfatases/fisiologia , Proteínas de Transporte de Cátions/fisiologia , Movimento Celular/fisiologia , Cobre/metabolismo , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Fator de Crescimento Derivado de Plaquetas/farmacologia , Animais , Aterosclerose/enzimologia , Aterosclerose/patologia , Células Cultivadas , ATPases Transportadoras de Cobre , Humanos , Masculino , Microdomínios da Membrana/enzimologia , Microdomínios da Membrana/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/patologia , Músculo Liso Vascular/fisiologia , Miócitos de Músculo Liso/patologia , Miócitos de Músculo Liso/fisiologia , Ratos , Ratos Sprague-Dawley
6.
Circ J ; 76(10): 2456-64, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22785618

RESUMO

BACKGROUND: Prostaglandin E(1) (PGE(1)), via cAMP, dilates the ductus arteriosus (DA). For patients with DA-dependent congenital heart disease (CHD), PGE(1) is the sole DA dilator that is used until surgery, but PGE(1) has a short duration of action, and frequently induces apnea. Most importantly, PGE(1) increases hyaluronan (HA) production, leading to intimal thickening (IT) and eventually DA stenosis after long-term use. The purpose of this study was therefore to investigate potential DA dilators, such as phosphodiesterase 3 (PDE3) inhibitors, as alternatives to PGE(1). METHODS AND RESULTS: Expression of PDE3a and PDE3b mRNAs in rat DA tissue was higher than in the pulmonary artery. I.p. milrinone (10 or 1mg/kg) or olprinone (5 or 0.5mg/kg) induced maximal dilatation of the DA lasting for up to 2h in rat neonates. In contrast, vasodilation induced by PGE(1) (10µg/kg) was diminished within 2h. No respiratory distress was observed with milrinone or olprinone. Most important, milrinone did not induce HA production, cell migration, or proliferation when applied to cultured rat DA smooth muscle cells. Further, high expression of both PDE3a and PDE3b was demonstrated in the human DA tissue of CHD patients. CONCLUSIONS: Because PDE3 inhibitors induced longer-lasting vasodilation without causing apnea or HA-mediated IT, they may be good alternatives to PGE(1) for patients with DA-dependent CHD.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/biossíntese , Permeabilidade do Canal Arterial/tratamento farmacológico , Permeabilidade do Canal Arterial/enzimologia , Canal Arterial/enzimologia , Canal Arterial/fisiopatologia , Músculo Liso Vascular/enzimologia , Inibidores da Fosfodiesterase 3/farmacologia , Vasodilatação/efeitos dos fármacos , Alprostadil/metabolismo , Animais , Animais Recém-Nascidos , Canal Arterial/patologia , Permeabilidade do Canal Arterial/patologia , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Recém-Nascido , Masculino , Músculo Liso Vascular/patologia , RNA Mensageiro/biossíntese , Ratos Wistar
7.
Sci Rep ; 12(1): 3850, 2022 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-35264623

RESUMO

Dementia is associated with a high risk of death and hospitalization among patients on hemodialysis (HD). We retrospectively evaluated the prevalence of mild cognitive impairment (MCI) in 421 patients on maintenance HD across nine facilities and investigated whether decreased handgrip strength was associated with decreased cognitive function. The Montreal Cognitive Assessment-Japan (MoCA-J) score and handgrip strength were measured. The mean age was 69.8 ± 11.2 years, and the median dialysis vintage 74.5 (IQR 30-150) months. The median MoCA-J score was 25 (IQR 21-27), and MCI was confirmed in 245 (58.2%) patients. Both the MoCA-J score and MoCA-J executive score were associated with age, history of cerebrovascular disease (CVA), and handgrip strength after adjustments. We found, among patients on HD aged under 70 years with a history of CVA, a handgrip strength < 90% (25.2 kg in males and 16.2 kg in females) correlated with significantly lower MoCA-J scores. A high prevalence of MCI and decreased handgrip strength were observed in patients on HD. Handgrip strength may be useful for the easy detection of MCI. A decrease in handgrip strength would allow for the early detection of MCI, especially among patients on HD aged under 70 years with a history of CVA.


Assuntos
Disfunção Cognitiva , Força da Mão , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Prevalência , Diálise Renal/efeitos adversos , Estudos Retrospectivos
8.
Am J Physiol Cell Physiol ; 298(3): C450-6, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19923424

RESUMO

Caveolin, a member of the membrane-anchoring protein family, accumulates various growth receptors in caveolae and inhibits their function. Upregulation of caveolin attenuates cellular proliferation and growth. However, the role of caveolin in regulating insulin signals remains controversial. Here, we demonstrate that caveolin potently enhances insulin receptor (IR) signaling when overexpressed in the liver in vivo. Adenovirus-mediated gene transfer was used to overexpress caveolin specifically in the liver of diabetic obese mice, which were generated with a high-fat diet. Expression of molecules involved in IR signaling, such as IR or Akt, remained unchanged after gene transfer. However, hepatic glycogen synthesis was markedly increased with a decrease in phosphoenolpyruvate carboxykinase protein expression. Insulin sensitivity was increased after caveolin gene transfer as determined by decreased blood glucose levels in response to insulin injection and fasting blood glucose levels. Glucose tolerant test performance was also improved. Similar improvements were obtained in KKA(y) genetically diabetic mice. Adenovirus-mediated overexpression of caveolin-3 in hepatic cells also enhanced IR signaling, as shown by increased phosphorylation of IR in response to insulin stimulation and higher glycogen synthesis at baseline. These effects were attributed mostly to increased insulin receptor activity and caveolin-mediated, direct inhibition of protein tyrosine phosphatase 1B, which was increased in obese mouse livers. In conclusion, our results suggest that caveolin is an important regulator of glucose metabolism that can enhance insulin signals.


Assuntos
Glicemia/metabolismo , Caveolina 3/metabolismo , Diabetes Mellitus Tipo 2/sangue , Técnicas de Transferência de Genes , Insulina/sangue , Fígado/metabolismo , Obesidade/complicações , Adenoviridae/genética , Fatores Etários , Envelhecimento/sangue , Animais , Glicemia/efeitos dos fármacos , Caveolina 3/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Diabetes Mellitus Tipo 2/terapia , Gorduras na Dieta , Modelos Animais de Doenças , Vetores Genéticos , Teste de Tolerância a Glucose , Glicogênio/biossíntese , Células Hep G2 , Humanos , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Resistência à Insulina , Fígado/efeitos dos fármacos , Camundongos , Obesidade/sangue , Obesidade/genética , Obesidade/fisiopatologia , Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismo , Fosforilação , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Ratos , Receptor de Insulina/metabolismo , Transdução de Sinais
9.
Clin Exp Hypertens ; 31(3): 259-70, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19387902

RESUMO

We examined risk factors for coronary heart disease (CHD) by ambulatory blood pressure (BP) monitoring in 72 diabetic hypertensives who were hospitalized for the educational program. The patients were divided into two groups (CHD group, 19 subjects; and non-CHD group, 53 subjects) along with or without co-existing CHD. On ambulatory BP monitoring, no significant differences were found between the groups regarding BP values through the day. However, the CHD group had a significantly greater BP variability than non-CHD group. The result of logistic regression analysis demonstrated that nighttime systolic BP variability was an independent risk factor for CHD.


Assuntos
Monitorização Ambulatorial da Pressão Arterial , Pressão Sanguínea/fisiologia , Ritmo Circadiano/fisiologia , Doença das Coronárias/epidemiologia , Complicações do Diabetes/complicações , Hipertensão/complicações , Idoso , Doença das Coronárias/fisiopatologia , Estudos Transversais , Complicações do Diabetes/fisiopatologia , Feminino , Humanos , Hipertensão/fisiopatologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fatores de Risco
10.
Cell Signal ; 17(10): 1175-82, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15913956

RESUMO

Caveolae, discovered by electron microscope in the 1950s, are membrane invaginations that accommodate various molecules that are involved in cellular signaling. Caveolin, a major protein component of caveolae identified in 1990s, has been known to inhibit the function of multiple caveolar proteins, such as kinases, which are involved in cell growth and proliferation, and thus considered to be a general growth signal inhibitor. Recent studies using transgenic mouse models have suggested that insulin signal may be exempted from this inhibition, which rather requires the presence of caveolin for proper signaling. Caveolin may stabilize insulin receptor protein or directly stimulate insulin receptors. Other studies have demonstrated that caveolae provide the TC10 complex with cellular microdomains for glucose transportation through Glut4. These findings suggest that caveolin plays an important role in insulin signal to maintain glucose metabolism in intact animals. However, the role of caveolin in insulin signal may differ from that in other transmembrane receptor signals.


Assuntos
Caveolinas/fisiologia , Receptor de Insulina/fisiologia , Transdução de Sinais/fisiologia , Animais , Cavéolas/fisiologia , Caveolinas/genética , Transportador de Glucose Tipo 4 , Humanos , Modelos Biológicos , Proteínas de Transporte de Monossacarídeos/fisiologia , Proteínas Musculares/fisiologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiologia , Proteínas rho de Ligação ao GTP/fisiologia
11.
Atherosclerosis ; 240(1): 297-304, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25818388

RESUMO

OBJECTIVE: There is no clinical evidence that supports the benefit of integrative medicine, defined as combination therapy of oriental and western medicine, on obesity-related hypertension. This study evaluates the efficacy of Bofu-tsusho-san (BOF), an oriental herbal medicine, on the ambulatory blood pressure (BP) profile in hypertensive patients with obesity. METHODS: The study design was a multicenter, randomized, open-label, parallel-group controlled trial in 107 hypertensive patients with obesity. Participants were randomly assigned to receive either the conventional control therapy or BOF add-on therapy. In both groups antihypertensive therapy was aimed at achieving the target clinic BP. The primary outcome was change in the ambulatory BP profile from baseline to 24 weeks after randomization. RESULTS: Daytime systolic BP variability, an important parameter of ambulatory BP profile, was decreased in the BOF group, and the difference in the changes in daytime systolic BP variability was significant between the BOF and control group (Control vs BOF; the change from baseline in daytime systolic BP variability, 1.0±3.3 vs -1.0±3.3%; p=0.006). CONCLUSION: The BOF add-on therapy effectively improved the ambulatory BP variability. This is the first report suggesting that an integrative medicine approach may exert favorable effects on obesity-related hypertension compared with conventional pharmaceutical treatment. CLINICAL TRIAL REGISTRATION: UMIN000003878.


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Medicamentos de Ervas Chinesas/uso terapêutico , Hipertensão/tratamento farmacológico , Obesidade/complicações , Idoso , Anti-Hipertensivos/efeitos adversos , Monitorização Ambulatorial da Pressão Arterial , Quimioterapia Combinada , Medicamentos de Ervas Chinesas/efeitos adversos , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/etiologia , Hipertensão/fisiopatologia , Japão , Masculino , Pessoa de Meia-Idade , Fitoterapia , Plantas Medicinais , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
12.
CEN Case Rep ; 3(1): 53-55, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-28509242

RESUMO

Nephrotic syndrome due to renovascular hypertension is uncommon. We herein report a case of nephrotic syndrome associated with unilateral atherosclerotic renal artery stenosis. A 76-year-old woman who had been taking antihypertensive medication for more than 15 years was referred to our hospital for treatment of uncontrolled hypertension and massive proteinuria in the nephrotic range. An abdominal bruit was heard, and laboratory findings showed high plasma renin activity and hypokalemia. Renal computed tomography angiography showed severe stenosis of the ostium of the right renal artery and an atrophic right kidney. The left renal artery was normal and the left kidney was compensatorily enlarged. After admission, we started treatment with an angiotensin II receptor blocker and subsequently performed percutaneous transluminal renal angioplasty with renal artery stent placement. As a result, her blood pressure became well controlled and the massive proteinuria disappeared. In addition, her stenotic-side renal atrophy was resolved, concomitant with an improvement in her renal function. The contralateral renal hypertrophy was also resolved.

13.
Diabetes ; 62(11): 3839-50, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23884884

RESUMO

Oxidative stress and endothelial dysfunction contribute to vascular complication in diabetes. Extracellular superoxide dismutase (SOD3) is one of the key antioxidant enzymes that obtains copper via copper transporter ATP7A. SOD3 is secreted from vascular smooth muscles cells (VSMCs) and anchors at the endothelial surface. The role of SOD3 and ATP7A in endothelial dysfunction in type 1 diabetes mellitus (T1DM) is entirely unknown. Here we show that the specific activity of SOD3, but not SOD1, is decreased, which is associated with increased O2(•-) production in aortas of streptozotocin-induced and genetically induced Ins2(Akita) T1DM mice. Exogenous copper partially rescued SOD3 activity in isolated T1DM vessels. Functionally, acetylcholine-induced, endothelium-dependent relaxation is impaired in T1DM mesenteric arteries, which is rescued by SOD mimetic tempol or gene transfer of SOD3. Mechanistically, ATP7A expression in T1DM vessels is dramatically decreased whereas other copper transport proteins are not altered. T1DM-induced endothelial dysfunction and decrease of SOD3 activity are rescued in transgenic mice overexpressing ATP7A. Furthermore, SOD3-deficient T1DM mice or ATP7A mutant T1DM mice augment endothelial dysfunction and vascular O2(•-) production versus T1DM mice. These effects are in part due to hypoinsulinemia in T1DM mice, since insulin treatment, but not high glucose, increases ATP7A expression in VSMCs and restores SOD3 activity in the organoid culture of T1DM vessels. In summary, a decrease in ATP7A protein expression contributes to impaired SOD3 activity, resulting in O2(•-) overproduction and endothelial dysfunction in blood vessels of T1DM. Thus, restoring copper transporter function is an essential therapeutic approach for oxidant stress-dependent vascular and metabolic diseases.


Assuntos
Adenosina Trifosfatases/fisiologia , Proteínas de Transporte de Cátions/fisiologia , Cobre/metabolismo , Superóxido Dismutase/metabolismo , Adenosina Trifosfatases/genética , Animais , Aorta/metabolismo , Proteínas de Transporte de Cátions/genética , Células Cultivadas , Cobre/farmacologia , ATPases Transportadoras de Cobre , Óxidos N-Cíclicos/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Insulina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Ratos , Marcadores de Spin , Superóxido Dismutase/genética , Superóxidos/metabolismo , Transfecção
14.
Intern Med ; 52(10): 1079-83, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23676594

RESUMO

The case of a 68-year-old woman with purpura nephritis associated with nephrotic syndrome is herein described. The patient's clinical course and the findings of a renal biopsy study revealed purpura nephritis. Following treatment with corticosteroids and intravenous cyclophosphamide accompanied by an angiotensin II type I receptor-blocker, an anti-platelet drug and an hydroxymethylglutaryl (HMG)-CoA, the proteinuria mildly decreased. Additional rituximab therapy led to a complete remission. This report describes our successful experience using rituximab to treat refractory nephrotic syndrome of purpura nephritis. Further studies are required to confirm the efficacy of rituximab as an alternative therapy for nephrotic syndrome.


Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Vasculite por IgA/tratamento farmacológico , Imunossupressores/uso terapêutico , Nefrite/etiologia , Síndrome Nefrótica/etiologia , Administração Oral , Idoso , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/uso terapêutico , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Quimioterapia Combinada , Feminino , Humanos , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/etiologia , Vasculite por IgA/complicações , Infusões Intravenosas , Metilprednisolona/administração & dosagem , Metilprednisolona/uso terapêutico , Nefrite/patologia , Síndrome Nefrótica/patologia , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/uso terapêutico , Prednisolona/administração & dosagem , Prednisolona/uso terapêutico , Proteinúria/etiologia , Indução de Remissão , Rituximab
15.
J Clin Hypertens (Greenwich) ; 14(8): 522-9, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22863160

RESUMO

Aliskiren is a direct renin inhibitor that exerts its effect at the rate-limiting step of the renin-angiotensin system. This study was performed to examine the beneficial effects of aliskiren-based antihypertensive therapy on the ambulatory blood pressure (BP) profile, central hemodybamics, and arterial stiffness in untreated Japanese patients with mild to moderate hypertension. Twenty-one Japanese nondiabetic patients with untreated mild to moderate essential hypertension were initially given aliskiren once daily at 150 mg, and the dose was titrated up to 300 mg as needed. After 12 weeks of aliskiren-based therapy, the clinic, ambulatory, and central BP values as well as brachial-ankle pulse wave velocity (baPWV) were all significantly decreased compared with baseline (clinic systolic BP, 151 ± 11 mm Hg vs 132 ± 11 mm Hg; clinic diastolic BP, 91 ± 13 mm Hg vs 82 ± 9 mm Hg; 24-hour systolic BP, 144 ± 12 mm Hg vs 133 ± 11 mm Hg; 24-hour diastolic BP, 88 ± 8 mm Hg vs 81 ± 9 mm Hg; central BP, 162 ± 16 mm Hg vs 148 ± 14 mm Hg; baPWV, 1625 ± 245 cm/s vs 1495 ± 199 cm/s; P<.05). These results show that aliskiren, as a first-line regimen, improves the ambulatory BP profile and may have protective vascular effects in Japanese nondiabetic patients with untreated mild to moderate essential hypertension.


Assuntos
Amidas/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Fumaratos/farmacologia , Hemodinâmica/efeitos dos fármacos , Hipertensão/fisiopatologia , Índice de Gravidade de Doença , Rigidez Vascular/efeitos dos fármacos , Idoso , Amidas/uso terapêutico , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/fisiologia , Monitorização Ambulatorial da Pressão Arterial , Relação Dose-Resposta a Droga , Feminino , Fumaratos/uso terapêutico , Hemodinâmica/fisiologia , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/etnologia , Japão , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Estudos Retrospectivos , Resultado do Tratamento , Rigidez Vascular/fisiologia
16.
PLoS One ; 5(10): e13440, 2010 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-20976168

RESUMO

BACKGROUND: Neovascularization is an important repair mechanism in response to ischemic injury and is dependent on inflammation, angiogenesis and reactive oxygen species (ROS). IQGAP1, an actin-binding scaffold protein, is a key regulator for actin cytoskeleton and motility. We previously demonstrated that IQGAP1 mediates vascular endothelial growth factor (VEGF)-induced ROS production and migration of cultured endothelial cells (ECs); however, its role in post-ischemic neovascularization is unknown. METHODOLOGY/PRINCIPAL FINDINGS: Ischemia was induced by left femoral artery ligation, which resulted in increased IQGAP1 expression in Mac3(+) macrophages and CD31(+) capillary-like ECs in ischemic legs. Mice lacking IQGAP1 exhibited a significant reduction in the post-ischemic neovascularization as evaluated by laser Doppler blood flow, capillary density and α-actin positive arterioles. Furthermore, IQGAP1(-/-) mice showed a decrease in macrophage infiltration and ROS production in ischemic muscles, leading to impaired muscle regeneration and increased necrosis and fibrosis. The numbers of bone marrow (BM)-derived cells in the peripheral blood were not affected in these knockout mice. BM transplantation revealed that IQGAP1 expressed in both BM-derived cells and tissue resident cells, such as ECs, is required for post-ischemic neovascularization. Moreover, thioglycollate-induced peritoneal macrophage recruitment and ROS production were inhibited in IQGAP1(-/-) mice. In vitro, IQGAP1(-/-) BM-derived macrophages showed inhibition of migration and adhesion capacity, which may explain the defective macrophage recruitment into the ischemic tissue in IQGAP1(-/-) mice. CONCLUSIONS/SIGNIFICANCE: IQGAP1 plays a key role in post-ischemic neovascularization by regulating, not only, ECs-mediated angiogenesis but also macrophage infiltration as well as ROS production. Thus, IQGAP1 is a potential therapeutic target for inflammation- and angiogenesis-dependent ischemic cardiovascular diseases.


Assuntos
Macrófagos/patologia , Neovascularização Patológica , Proteínas Ativadoras de ras GTPase/fisiologia , Animais , Camundongos , Camundongos Knockout , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Ativadoras de ras GTPase/genética
17.
PLoS One ; 5(4): e10189, 2010 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-20422004

RESUMO

Reactive oxygen species (ROS), in particular, H(2)O(2), is essential for full activation of VEGF receptor2 (VEGFR2) signaling involved in endothelial cell (EC) proliferation and migration. Extracellular superoxide dismutase (ecSOD) is a major secreted extracellular enzyme that catalyzes the dismutation of superoxide to H(2)O(2), and anchors to EC surface through heparin-binding domain (HBD). Mice lacking ecSOD show impaired postnatal angiogenesis. However, it is unknown whether ecSOD-derived H(2)O(2) regulates VEGF signaling. Here we show that gene transfer of ecSOD, but not ecSOD lacking HBD (ecSOD-DeltaHBD), increases H(2)O(2) levels in adductor muscle of mice, and promotes angiogenesis after hindlimb ischemia. Mice lacking ecSOD show reduction of H(2)O(2) in non-ischemic and ischemic limbs. In vitro, overexpression of ecSOD, but not ecSOD-DeltaHBD, in cultured medium in ECs enhances VEGF-induced tyrosine phosphorylation of VEGFR2 (VEGFR2-pY), which is prevented by short-term pretreatment with catalase that scavenges extracellular H(2)O(2). Either exogenous H(2)O(2) (<500 microM), which is diffusible, or nitric oxide donor has no effect on VEGF-induced VEGFR2-pY. These suggest that ecSOD binding to ECs via HBD is required for localized generation of extracellular H(2)O(2) to regulate VEGFR2-pY. Mechanistically, VEGF-induced VEGFR2-pY in caveolae/lipid rafts, but non-lipid rafts, is enhanced by ecSOD, which localizes at lipid rafts via HBD. One of the targets of ROS is protein tyrosine phosphatases (PTPs). ecSOD induces oxidation and inactivation of both PTP1B and DEP1, which negatively regulates VEGFR2-pY, in caveolae/lipid rafts, but not non-lipid rafts. Disruption of caveolae/lipid rafts, or PTPs inhibitor orthovanadate, or siRNAs for PTP1B and DEP1 enhances VEGF-induced VEGFR2-pY, which prevents ecSOD-induced effect. Functionally, ecSOD promotes VEGF-stimulated EC migration and proliferation. In summary, extracellular H(2)O(2) generated by ecSOD localized at caveolae/lipid rafts via HBD promotes VEGFR2 signaling via oxidative inactivation of PTPs in these microdomains. Thus, ecSOD is a potential therapeutic target for angiogenesis-dependent cardiovascular diseases.


Assuntos
Cavéolas/metabolismo , Peróxido de Hidrogênio/metabolismo , Isquemia/patologia , Neovascularização Fisiológica , Superóxido Dismutase/metabolismo , Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Movimento Celular , Proliferação de Células , Células Endoteliais/citologia , Microdomínios da Membrana/metabolismo , Camundongos , Oxirredução , Fosforilação , Transdução de Sinais , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
18.
Clin Exp Nephrol ; 12(3): 224-7, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18224274

RESUMO

A 65-year-old woman with a 48-year history of Behçet's disease associated with nephrotic syndrome is described. Immunofluorescence study revealed IgA nephropathy. Following treatment with an angiotensin II type-I receptor-blocker, an anti-platelet drug, and an HMG-CoA reductase inhibitor, accompanied by dietary restrictions of protein and sodium, proteinuria was markedly decreased. This report describes our experience with a rare entity of Behçet's disease complicated by nephrotic syndrome due to IgA nephropathy. Routine urine examination and renal biopsy are needed for the detection and diagnosis of renal problems with Behçet's disease.


Assuntos
Síndrome de Behçet/complicações , Síndrome de Behçet/diagnóstico , Glomerulonefrite por IGA/complicações , Síndrome Nefrótica/complicações , Síndrome Nefrótica/diagnóstico , Idoso , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Atorvastatina , Síndrome de Behçet/tratamento farmacológico , Benzimidazóis/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Dilazep/uso terapêutico , Quimioterapia Combinada , Feminino , Ácidos Heptanoicos/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Síndrome Nefrótica/etiologia , Pirróis/uso terapêutico , Tetrazóis/uso terapêutico , Vasodilatadores/uso terapêutico
19.
J Cell Mol Med ; 10(1): 216-24, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16563233

RESUMO

Caveolin, a major protein component of caveolae, directly interacts with multiple signaling molecules, such as Ras and growth factor receptors, and inhibits their function. However, the role of the second messenger system in mediating this inhibition by caveolin remains poorly understood. We examined the role of Ca2+-dependent signal in caveolin- mediated growth inhibition using a rat cardiac myoblast cell line (H9C2), in which the expression of caveolin- 3, the muscle specific subtype, can be induced using the LacSwitch system. Upon induction with IPTG and serum-starvation, the expression of caveolin-3 was increased by 3.3-fold relative to that of mock-induced cells. The recombinant caveolin-3 was localized to the same subcellular fraction as endogenous caveolin-3 after sucrose gradient purification. Angiotensin II enhanced ERK phosphorylation, but this enhancement was significantly decreased in caveolin-3-induced cells in comparison to that in mock-induced cells. Similarly, when cells were stimulated with fetal calf serum, DNA synthesis, as determined by [3H]-thymidine incorporation, was significantly decreased in caveolin- 3-induced cells. When cells were treated with Ca2+ chelator (BAPTA and EGTA), however, this attenuation was blunted. Calphostin (PKC inhibitor), but not cyclosporine A treatment (calcineurin inhibitor), blunted this attenuation in caveolin-3 induced cells. Our findings suggest that caveolin exhibits growth inhibition in a Ca2+-dependent manner, most likely through PKC, in cardiac myoblasts.


Assuntos
Cálcio/metabolismo , Caveolina 3/metabolismo , Mioblastos Cardíacos/metabolismo , Transdução de Sinais , Angiotensinas/metabolismo , Animais , Inibidores de Calcineurina , Cavéolas/fisiologia , Linhagem Celular , Proliferação de Células , Células Clonais , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteína Quinase C/antagonistas & inibidores , Ratos
20.
Am J Physiol Cell Physiol ; 285(3): C567-74, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12748066

RESUMO

Neuronal nicotinic acetylcholine receptors (nAChRs) are made of multiple subunits with diversified functions. The nAChR alpha 7-subunit has a property of high Ca2+ permeability and may have specific functions and localization within the plasma membrane as a signal transduction molecule. In PC-12 cells, fractionation by sucrose gradient centrifugation revealed that nAChR alpha 7 existed in low-density, cholesterol-enriched plasma membrane microdomains known as lipid rafts where flotillin also exists. In contrast, nAChR alpha 5- and beta2-subunits were located in high-density fractions, out of the lipid rafts. Type 6 adenylyl cyclase (AC6), a calcium-inhibitable isoform, was also found in lipid rafts and was coimmunoprecipitated with nAChR alpha 7. Cholesterol depletion from plasma membranes with methyl-beta-cyclodextrin redistributed nAChR alpha 7 and AC6 diffusely within plasma membranes. Nicotine stimulation reduced forskolin-stimulated AC activity by 35%, and this inhibition was negated by either treatment with alpha-bungarotoxin, a specific antagonist of nAChR alpha 7, or cholesterol depletion from plasma membranes. The effect of cholesterol depletion was negated by the addition of cholesterol. These data suggest that nAChR alpha 7 has a specific membrane localization relative to other nAChR subunits and that lipid rafts are necessary to localize nAChR alpha 7 with AC within plasma membranes. In addition, nAChR alpha 7 may regulate the AC activity via Ca2+ within lipid rafts.


Assuntos
AMP Cíclico/metabolismo , Microdomínios da Membrana/metabolismo , Receptores Nicotínicos/metabolismo , Adenilil Ciclases/metabolismo , Animais , Colesterol/metabolismo , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Células PC12 , Ratos , Receptor Nicotínico de Acetilcolina alfa7
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