基本情報
- 所属
- 自治医科大学 腎臓内科学部門/栃木県南那須地域医療講座 特命教授
- 学位
- 医学博士(東京大学)
- J-GLOBAL ID
- 201901020904598409
- researchmap会員ID
- B000380185
1997年 東京大学医学部医学科卒業、医師免許取得
2004年 東京大学医学系研究科博士課程（内科学） 学位取得
研究分野
1論文
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Internal medicine (Tokyo, Japan) 2024年3月4日A 79-year-old male patient with type 2 diabetic nephropathy and hypertension was admitted to our hospital because of acute kidney injury with significantly elevated serum creatinine (8.12 mg/dL) and urinary β2-microglobulin (β2MG, 31,748 μg/L) levels. α-Glucosidase inhibitor (α-GI) miglitol, started two weeks prior to presentation, was discontinued because drug-induced acute interstitial nephritis (AIN) was suspected. Renal biopsy revealed AIN and diabetic nephropathy. The drug-induced lymphocyte stimulation test for miglitol was also positive. After the discontinuation of miglitol, the urinary β2MG levels decreased to the normal range. This case raises the possibility that α-GI miglitol can worsen the renal function in patients with underlying renal dysfunction.
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Dokkyo Journal of Medical Sciences 49(1) 9-15 2022年7月高血圧治療ガイドラインでは,診察室血圧(OBP)は1-2分間隔で測定を繰り返し,安定した2回の測定値の平均で評価することとされているが,数多い高血圧患者の実地診療において測定を繰り返すことは難しく,1回の測定で評価される場合も多い.本研究では診察室血圧が高値を呈する高血圧患者において,深呼吸後に測定を繰り返すことによる血圧の変化を検討した.外来を受診した高血圧患者で,診察室の収縮期血圧(SBP)140mmHg以上を呈した160名を対象とした.1回目の測定の後,深呼吸を繰り返し1-2分後に2回目の測定を行い,血圧の変化に関係する因子を検討した.1回目のOBPは147/84mmHgであったが,2回目は136/82mmHgと平均11/2mmHg低下し,69%が非高血圧となった.SBPが10mmHg以上低下したR群(91名)と10mmHg未満のN群(69名)の比較では,R群の方が血清クレアチニン(sCr)が低く(1.03 vs 1.36mg/dL,p=0.018)血中ヘモグロビン(Hb)が高値(13.9 vs 13.1g/dL,p=0.012)で,SBPの低下とHbの間には負の相関が認められた(r=-0.157,p=0.046).SBPが140未満に低下した110例ではしなかった50例に比べ,家庭血圧で夜のSBPが低く,HbやeGFR(62.3 vs 52.1mL/分/1.73m2,p=0.021)が高値で,sCrやアルブミン尿(124 vs 425mg/gCr,p=0.025)が低値であった.外来加療中の高血圧患者で診察室血圧が高値である場合,特に腎機能低下や蛋白尿がなければ,多くは深呼吸を繰り返すことにより正常化するため,治療方針を決める際に考慮するべきであると思われる.(著者抄録)
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International journal of molecular sciences 22(24) 2021年12月14日In minimal change nephrotic syndrome, podocyte vesicle transport is enhanced. Adenomatous polyposis coli (APC) anchors microtubules to cell membranes and plays an important role in vesicle transport. To clarify the role of APC in vesicle transport in podocytes, nephrotic syndrome was induced by puromycin amino nucleoside (PAN) injection in mice expressing APC1638T lacking the C-terminal of microtubule-binding site (APC1638T mouse); this was examined in renal tissue changes. The kidney size and glomerular area of APC1638T mice were reduced (p = 0.014); however, the number of podocytes was same between wild-type (WT) mice and APC1638T mice. The ultrastructure of podocyte foot process was normal by electron microscopy. When nephrotic syndrome was induced, the kidneys of WT+PAN mice became swollen with many hyaline casts, whereas these changes were inhibited in the kidneys of APC1638T+PAN mice. Electron microscopy showed foot process effacement in both groups; however, APC1638T+PAN mice had fewer vesicles in the basal area of podocytes than WT+PAN mice. Cytoplasmic dynein-1, a motor protein for vesicle transport, and α-tubulin were significantly reduced in APC1638T+PAN mice associated with suppressed urinary albumin excretion compared to WT+PAN mice. In conclusion, APC1638T mice showed reduced albuminuria associated with suppressed podocyte vesicle transport when minimal change nephrotic syndrome was induced.
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Renal Replacement Therapy 7(1) 2021年12月<title>Abstract</title><sec> <title>Background</title> Though treatment of anemia in chronic kidney disease (CKD) patients has been improved remarkably by erythropoiesis-stimulating agents (ESA), hypo-responsiveness to ESA poses a persistent problem in a subgroup of CKD patients, especially those on dialysis, with deteriorated mortality or cardiovascular risks. Pathomechanism of this condition including cardiovascular implications has not been sufficiently investigated. </sec><sec> <title>Methods</title> Clinical parameters of 101 chronic hemodialysis patients which included those hospitalized in our university hospital were examined cross-sectionally. As a marker estimating ESA hypo-responsiveness, erythropoietin resistance index (ERI) was calculated. Numbers of circulating endothelial progenitor cells (EPC) were measured by flow cytometry. Associations among values were analyzed by methods including multiple linear regression. </sec><sec> <title>Results</title> Majority (93%) of the subjects were hospitalized patients with various comorbidities. ERI (18.4 [7.2–33.0] IU/week/kg/g/dL) and ESA dose (161.6 [75.0–320.9] IU/week/kg) of all the subjects were relatively high. Factors negatively correlated with EPC included age, HD vintage, CRP, pulse rate, ESA dose and ERI, while male sex and systolic blood pressure were positively correlated. By multiple linear regression analysis, age, sex and ERI (standardized coefficient beta − 0.202, <italic>p</italic> = 0.039) remained as the independently predicting factors of EPC (log CD133/Flk1+ EPC). Darbepoetin alpha was used in 65 patients, especially predominant when requiring higher ESA doses, but by correlation or multivariable analyses, this did not substantially modify the negative association between ERI and EPC. </sec><sec> <title>Conclusions</title> ERI was independently associated with EPC paucity in a cohort with various comorbidities. This may suggest a link which connects ESA hypo-responsiveness to compromised cardiovascular prognosis of dialysis patients. </sec>
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Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 141 111901-111901 2021年7月15日INTRODUCTION: Eucommia ulmoides leaves are used as Tochu tea, which has a blood pressure lowering effect of unknown mechanism. PURPOSE AND METHODS: The effects of Tochu tea and its component, geniposidic acid, on blood pressure and renal hemodynamics were investigated in Dahl salt-sensitive (DS) rats received 1% saline solution from 4 weeks of age. At 9 weeks of age, 1% saline alone (DSHS), Tochu tea extract added 1% saline (DSHS+T), or geniposidic acid added 1% saline (DSHS+G) was administered for another 4 weeks. DS rats fed with tap water were used as controls (DSLS). At 13 weeks, the blood pressure, the renal plasma flow (RPF) and the renal NADPH oxidase, endothelial nitric oxide synthase (eNOS) were examined. RESULTS: Blood pressure in DSHS rats was significantly increased in comparison to DSLS (144 vs. 196 mmHg, p < 0.01), and was significantly reduced in DSHS+T (158 mmHg) and DSHS+G (162 mmHg) rats. RPF in DSHS+T rats was significantly higher than in DSHS rats (p < 0.05). The expression of NADPH oxidase in DSHS rats was enhanced in comparison to DSLS rats; however, it was suppressed in DSHS+T and DSHS+G rats, and the NO production by eNOS was increased; thus, RPF was improved. The urinary Na excretion in DSHS rats was higher than that in DSLS rats; however it was further increased in DSHS+T rats without changes in the tubular Na transporters. CONCLUSION: Tochu tea and geniposidic acid suppressed NADPH oxidase, increased eNOS, and improved blood pressure and renal hemodynamics.
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Dokkyo Journal of Medical Sciences 48(3) 171-181 2021年Patients with chronic kidney disease（CKD）are at high risk for developing cardiovascular diseases, and hyperuricemia is associated with the progression of renal dysfunction and the incidence of cardiovascular events. Allopurinol（Alp）, a xanthine oxidase inhibitor（XOi）, has been shown to improve the prognosis of CKD patients by inhibiting renal dysfunction and cardiovascular events. However, Alp possibly causes some serious side effects especially in patients with impaired renal function. Newer XOi such as febuxostat and topiroxostat（Tpx）can be safely used in CKD patients, while it has been reported that the incidence of cardiovascular death was rather higher in gout patients with cardiovascular diseases given febuxostat than those given Alp. In this study, we compared the effects of Alp and Tpx on cardiovascular risk profile in CKD patients. Thirty-five CKD patients were given Alp（50, 100, 200 mg/day）or Tpx（40, 80, 160 mg/ day）for 3-6 months in a random crossover manner, and the indices of cardiovascular risk were evaluated at the end of each treatment period. Hypouricemic effect was more prominent in Tpx than Alp（5.8 vs 6.4 mg/dL, p＝0.001）. There were significant differences in systolic blood pressure（Tpx 122 vs Alp 127 mmHg, p＝0.004）, serum creatinine（1.72 vs 1.93 mg/dL, p＝0.002）, plasma brain natriuretic peptide（43 vs 63 pg/mL, p＝0.022）, and the parameter of oxidative stress（reactive oxygen metabolite：314 vs 342 U. CARR, p＝0.010）. However, serum LDL-cholesterol（113 vs 102 mg/dL, p＝0.008）were significantly higher in Tpx than in Alp. Although attention should be paid to the effects on serum lipid profile, Tpx is supposedly more effective in inhibiting cardiovascular disorders and slowing the progression of renal dysfunction in hyperuricemic CKD patients.
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International journal of environmental research and public health 17(11) 2020年6月5日 査読有りThe association of gestational hypertension (GH) with future hypertension in Japanese women is unclear. Hence, this study aimed to examine the association between GH and the risk of future hypertension in middle-aged-to-older Japanese women. A case-control study was performed, including 62 hypertensive women (case) and 75 nonhypertensive women (control). GH during the first pregnancy was diagnosed on the basis of the Maternal and Child Health Handbook record. Hypertensive women were recruited from outpatients in the hospital and residents who completed an annual health check-up in a community. Hypertension was defined as blood pressure with systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg, or taking antihypertensive medications. The average age (SD) of the cases and controls at the time of recruitment was 63.1 (8.4) and 57.7 (9.4), respectively. The multivariable-adjusted odds ratio of GH for hypertension in middle-aged-to-older women was 4.2 (95% confidence interval, 1.0-17.5) after adjustment for potential confounding factors such as age and body-mass index (BMI) upon recruitment, prepregnancy BMI, and age at first delivery. In conclusion, GH can be an independent risk factor for future hypertension among Japanese women.
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Hypertension research : official journal of the Japanese Society of Hypertension 2020年5月8日 査読有りVacuolar H+-adenosine triphosphatase (V-ATPase) stimulates vesicular acidification that may activate cytoplasmic enzymes, hormone secretion and membrane recycling of transporters. We investigated the effect of blockade of V-ATPase by bafilomycin B1 on renal gluconeogenesis, mitochondrial enzymes, and insulin secretion in type 2 diabetic rats. Spontaneous type 2 diabetic Torii rats were treated with intraperitoneal injection of bafilomycin B1 for 1 week, and the kidneys were examined after 24 h of starvation in metabolic cages. The renal expression and activity of V-ATPase were increased in the brush border membrane of the proximal tubules in diabetic rats. The blockade of V-ATPase by bafilomycin B1 reduced renal V-ATPase activity and urinary ammonium in diabetic rats. Treatment with bafilomycin suppressed the enhanced renal gluconeogenesis enzymes and mitochondrial electron transport enzymes in type 2 diabetic rats and reduced the renal cytoplasmic glucose levels. The insulin index and pancreatic insulin granules were decreased in diabetic rats with increased V-ATPase expression in islet cells, and treatment with bafilomycin B1 reversed these changes and increased the insulin secretion index. Hepatosteatosis in type 2 diabetic rats was ameliorated by bafilomycin treatment. As a consequence, treatment with bafilomycin B1 significantly decreased the plasma glucose level after 24 h of starvation in diabetic rats. In conclusion, a V-ATPase inhibitor improved plasma glucose levels in type 2 diabetes by inhibiting renal mitochondrial gluconeogenesis and improving insulin secretion.
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Dokkyo Journal of Medical Sciences 47(3) 145-151 2020年It has been demonstrated that home blood pressure is more predictive of the incidence of cardiovascular events than office blood pressure in general population and hyper-tensive patients. It seems generally accepted to measure blood pressure（BP）by automatic sphygmomanometer in the arm wearing shirt with thin sleeves, however, it is unknown how exactly the BP can be measured by automatic sphygmomanometer in arms wearing coat sleeves with various thickness. In this study, BPs were simultane-ously measured in the bare right arm and the left arm wearing a shirt or a coat by two automatic sphygmoma-nometers of same model type, and the measured values were compared. The average difference in BP between the two arms was small（0.7/0.2 mmHg）. However, there observed a significant reduction in BP with a lapse of time （ −4.2/−2.1 mmHg）. The measured BP values by the two automatic sphygmomanometers were quite comparable and the average difference was negligible（0.3/− 0.4 mmHg）. Wearing a shirt did not significantly affect the measured BP values（−1.5/0.3 mmHg）, however, the sleeves of coats produced the measured BP value difference of −4.2/1.3 mmHg in average and the difference in systolic BP was significant（p＝0.003）. It is concluded that, in the BP measurements using automatic sphygmomanom-eters, wearing a shirt does not significantly affect the measured BP values, however, wearing a coat significantly lowers the measured value of systolic BP.
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MEDICINE 98(44) e17801 2019年11月 査読有りRationale: Anti-glomerular basement membrane (GBM) disease is a T cell-mediated disease that has a poor prognosis with conventional therapy. We tested rituximab as a primary therapy to reduce anti-GBM antibody produced by B cells.Patient concerns: A 53-year old woman with complaints of a fever, headache and abdominal discomfort showed renal failure with elevated anti-GBM antibody, and renal biopsy revealed crescentic necrotizing glomerulonephritis with linear immunoglobulin G (IgG) 1 deposition along GBM.Diagnoses: The patient's plasma contained autoantibodies against Goodpasture antigen, which is the NC domain of collagen IVa3, and CD4-positive helper T cells were found surrounding crescent glomeruli with the coexistence CD20-positive B cells.Interventions: Rituximab with steroid and plasma exchange.Outcomes: The levels of autoantibody for Goodpasture antigen were reduced, and the patient was able to temporarily withdraw from hemodialysis.Lessons: B cell depletion with rituximab is effective as an initial therapy for anti-GBM disease.
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Hypertension research : official journal of the Japanese Society of Hypertension 42(4) 483-495 2019年4月 査読有りOptimal blood pressure (BP) targets for hypertension have been an important clinical issue but have been elusive. The Systolic Blood Pressure Intervention Trial (SPRINT) showed significant benefits of intensive BP-lowering treatment with a target systolic BP level of < 120 mm Hg on major cardiovascular (CV) events and mortality, whereas there was a modest increase in renal events related to BP-lowering treatment. We searched the PubMed, Cochrane CENTRAL, and ICHUSHI databases for randomized trials that assigned participants to intensive versus usual BP-lowering treatment with different BP targets. The outcomes were major CV events, all-cause death, myocardial infarction, stroke, heart failure, renal events, and adverse events. Nineteen trials that enrolled a total of 55,529 participants with a mean follow-up duration ranging from 1.6 to 12.2 years were included in the present analysis. There was a significant reduction in major CV events, myocardial infarction, and stroke and a trend toward a reduction in heart failure associated with intensive BP-lowering treatment, but no differences in the risks of all-cause death, renal events, or adverse events were observed between the randomized groups. Subgroup analyses indicated that intensive BP-lowering treatment with a target of < 130/80 mm Hg and/or achievement of BP < 130/80 mm Hg were associated with a significant reduction in major CV events compared with the usual group. In conclusion, intensive BP-lowering treatment reduces the risk of CV events. A target BP level of < 130/80 mm Hg appears to be optimal for CV protection in patients with hypertension.
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CLINICAL AND EXPERIMENTAL NEPHROLOGY 23(1) 1-15 2019年1月
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American journal of physiology. Heart and circulatory physiology 308(8) H853-61-61 2015年4月15日 査読有りAntiplatelet drugs, frequently used for cardiovascular events with thrombotic involvement, are also regarded as possible promising agents for cardiovascular primary prevention. The roles of P2Y12, an ADP receptor and the target of thienopyridine antiplatelet drugs, are not satisfactorily known in the vascular wall. We investigated the hypothesis that vascular smooth muscle cell (VSMC) P2Y12 is involved in vascular wall inflammatory changes by upregulating monocyte chemoattractant protein-1 (MCP-1) and promoting monocyte adhesion. ADP at 10(-5) M induced a 3.6 ± 0.3-fold upregulation of MCP-1 mRNA in cultured rat VSMCs, which was significantly inhibited by R-138727, the active metabolite of P2Y12 inhibitor prasugrel and siRNAs against P2Y12. ADP also induced MCP-1 protein upregulation, which was diminished by R-138727 and P2Y12 siRNAs. JNK (c-Jun NH2-terminal kinase) inhibition attenuated ADP-induced MCP-1 mRNA and protein upregulation. R-138727 and P2Y12 siRNAs inhibited ADP-induced JNK activation. The reactive oxygen species (ROS) inhibitors N-acetylcysteine (NAC), diphenyleneiodonium (DPI), and Tempol also diminished MCP-1 upregulation and JNK activation induced by ADP. ADP induced MCP-1 promoter activation, which was inhibited by R-138727 and P2Y12 siRNAs. Nuclear factor-κB (NF-κB) consensus sites in the MCP-1 promoter region were involved in this activation. ADP-induced NF-κB pathway activation, examined by a plasmid containing multiple NF-κB sites, was diminished by P2Y12 inhibition. For cellular function analysis, stimulation of VSMC with ADP increased subsequent THP-1 monocyte adhesion. P2Y12 siRNAs and CCR2 antagonism diminished this ADP-induced monocyte adhesion. These data suggested that ADP, via the VSMC P2Y12 receptor, induces vascular inflammatory changes by upregulating MCP-1 and promoting monocyte adhesion.
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Clinical and experimental nephrology 18(5) 704-10 2014年10月 査読有りBACKGROUD: Chronic kidney disease (CKD) is a staple risk factor not only for renal failure but also for cardiovascular diseases. In addition, because dyslipidemia facilitates atherosclerosis and renal dysfunction, antihyperlipidemic treatment is important to prevent cardiac and renal events in CKD patients. METHODS: We compared the effects of a statin and an intestinal cholesterol transporter inhibitor in 20 dyslipidemic patients with CKD presenting with proteinuria and/or glomerular filtration rate <60 mL/min/1.73 m(2). Either 5-10 mg atorvastatin or 10 mg ezetimibe was given for 3 months each in a randomized crossover manner and the parameters of oxidative stress, inflammation and endothelial function were compared. RESULTS: Atorvastatin lowered serum low-density lipoprotein (LDL) cholesterol more prominently than ezetimibe (103 ± 38 vs 130 ± 45 mg/dL, p < 0.001), while serum γ-glutamyl transpeptidase was higher in atorvastatin than in ezetimibe (29 ± 16 vs 25 ± 11 U/L, p = 0.013). On the other hand, serum oxidized LDL and high-sensitivity C-reactive protein were lower in the atorvastatin treatment period than in the ezetimibe treatment period (109 ± 38 vs 146 ± 67 U/L, p = 0.002; 1.02 ± 1.46 vs 1.47 ± 1.77 µg/mL, p = 0.003). Although serum adiponectin was not significantly different between the two drugs, the reactive hyperemia index, an index of endothelial function, was higher in atorvastatin than in ezetimibe (1.94 ± 0.58 vs 1.60 ± 0.44, p = 0.023). CONCLUSION: It is concluded that atorvastatin is more potent than ezetimibe in improving the serum lipid profile, reducing oxidative stress, suppressing inflammation and preserving endothelial function, while ezetimibe may be advantageous in reducing the hepatic lipid load.
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PloS one 9(5) e96948 2014年 査読有りBecause endothelial nitric oxide synthase (eNOS) has anti-inflammatory and anti-arteriosclerotic functions, it has been recognized as one of the key molecules essential for the homeostatic control of blood vessels other than relaxation of vascular tone. Here, we examined whether telmisartan modulates eNOS function through its pleiotropic effect. Administration of telmisartan to mice significantly increased the phosphorylation level of eNOS (Ser1177) in the aortic endothelium, but administration of valsartan had no effect. Similarly, telmisartan treatment of human umbilical vein endothelial cells significantly increased the phosphorylation levels of AMP-activated protein kinase (Thr172) and eNOS and the concentration of intracellular guanosine 3',5'-cyclic monophosphate (cGMP). Furthermore, pretreatment with a p38 mitogen-activated protein kinase (p38 MAPK) inhibitor suppressed the increased phosphorylation level of eNOS and intracellular cGMP concentration. These data show that telmisartan increases eNOS activity through Ser1177 phosphorylation in vascular endothelial cells mainly via p38 MAPK signaling.
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ASAIO JOURNAL 59(3) 284-285 2013年5月 査読有りNon-anticoagulant hemodialysis is conducted occasionally at limited numbers of hospitals on an empirical basis. This study examines the efficacy of polysulfone and vitamin E-bonded polysulfone dialyzer for non-anticoagulant hemodialysis. These dialyzers were assigned one after the other for a vintage hemodialysis patient complicated with uncontrollable bleeding. The patient's vital and console data throughout non-anticoagulant hemodialysis were monitored serially. Both dialyzers were reasonably applicable to hemodialysis without major clotting. The scheduled treatment period was completed. Vitamin E-bonded polysulfone dialyzer was superior to non-anticoagulant hemodialysis based on venous pressure observed during treatment.
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Hypertension research : official journal of the Japanese Society of Hypertension 34(12) 1283-7 2011年12月 査読有りOsteopontin (OPN) is known to be one of the cytokines that is involved in the vascular inflammation caused by aldosterone (Aldo). Previous reports have shown that Aldo increases OPN transcripts, and the mechanisms for this remain to be clarified. In this study, we investigated how Aldo increases OPN transcripts in the vascular smooth muscle cells of rats. Aldosterone increased OPN transcripts time-dependently as well as dose-dependently. This increase was diminished by eplerenone, a mineralocorticoid receptor (MR) antagonist. Luciferase promoter assays showed that the OPN promoter deleted to the -1599 site retained the same promoting ability as the full-length OPN promoter when stimulated by 10(-7) M Aldo, but the promoter deleted to the -1300 site lost the promoting ability. A glucocorticoid response element (GRE) is located in that deleted region. Luciferase assays of a mutated promoter without the GRE lost the luciferase upregulation, although mutated promoters with the deletion of other consensus sites maintained the promoter activity. The binding of the Aldo-MR complex to the GRE fragment was confirmed by an electrophoretic-mobility shift assay. This is the first report showing that Aldo regulates the transcriptional levels of OPN and inflammatory responses in the vasculature through a specific GRE site in the OPN promoter region.
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ASAIO JOURNAL 56(4) 323-325 2010年7月 査読有りPlatelet-derived microparticles (PDMPs) are released from activated platelets and are closely related to various diseases. Using the enzyme-linked immunosorbent assay, PDMP concentrations in blood and separated plasma of eight patients who underwent apheresis using membrane plasma separator at our hospital were tested. Considerable amounts of PDMPs were filtrated using plasma separators. However, the concentrations of PDMPs within the blood at the end of the therapy did not differ significantly from those before the session. Plasmapheresis itself might have activated platelets to release PDMPs or perhaps PDMPs within the supplementary fluid increased PDMPs during the therapy. After resolving these points, plasmapheresis could become an effective therapy against elevated PDMP conditions. ASAIO Journal 2010; 56:323-325.
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Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy 14(3) 287-91 2010年6月 査読有りFactor XIII (FXIII) deficiency increases the chance for pathological bleeding, but this disorder cannot be detected by routine laboratory tests. Virus removal and eradication (VRAD, the trademark of Asahikasei Kuraray Medical) by double filtration plasmapheresis (DFPP) is an effective technique used to eradicate the hepatitis C virus in people afflicted with the disease. We have previously reported that DFPP significantly reduced FXIII in those undergoing this treatment. VRAD is a modified type of DFPP with a larger pore size of the second filter compared to conventional DFPP. Because VRAD may have similar effects on FXIII levels, we investigated the kinetics of FXIII during the course of VRAD therapy. A retrospective, observational study of the patients who underwent VRAD between July 2008 and May 2009 was performed. Reduction ratios and sieving coefficients of FXIII and other marker proteins were examined. FXIII levels were decreased to 20% after each therapy. The reduction ratio and sieving coefficients of FXIII were between those of IgG (0.4-0.5) and LDL cholesterol (0.35). Similar to other blood purification therapies, therapeutic intensity, molecular weight, and half life are crucial factors for solute removal. Although the coexistence of liver disease might modify the course of FXIII during VRAD, the therapy itself effectively reduced FXIII levels. FXIII levels should be closely monitored during VRAD in order to reduce the chance of negative clinical sequelae.
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Hypertension research : official journal of the Japanese Society of Hypertension 32(2) 133-9 2009年2月 査読有りThe inhibition of apoptotic changes in vascular endothelial cells is important for preventing vascular damage from hypoxia. AMP-activated protein kinase (AMPK) has recently been identified as playing a role in vascular protection. Although the chemical reagent 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) has been used to stimulate AMPK activity, AICAR has been associated with several nonspecific reactions. We therefore constructed a new constitutively active mutant of AMPK alpha 1 (NcaAMPK), which lacks the autoinhibitory domain in AMPK alpha 1 and in which threonine 172 has been replaced with aspartate. We investigated whether NcaAMPK has an anti-apoptotic effect in vascular endothelial cells under anoxic conditions. NcaAMPK, or green fluorescent protein (GFP) as a control, was overexpressed in human umbilical vein endothelial cells (HUVECs). After HUVECs were incubated for 40 h under normoxic or anoxic conditions, we examined cell viability, caspase 3/7 activity, and expression and phosphorylation levels of apoptosis-related proteins. Cell viabilities under anoxic conditions were improved in NcaAMPK-overexpressing cells. Anoxia increased caspase 3/7 activity, but NcaAMPK reduced this increase significantly. NcaAMPK overexpression increased protein kinase B/Akt Ser473 and endothelial nitric oxide synthase Ser1177 phosphorylation, but pretreatment with the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) did not decrease the viability of NcaAMPK-overexpressing HUVECs. Furthermore, co-expression of a dominant-negative Akt reduced the improvement in cell viability and the suppression of poly (ADP-ribose) polymerase cleavage by NcaAMPK under anoxic conditions. In conclusion, NcaAMPK inhibited anoxia-induced apoptosis in vascular endothelial cells through Akt activation, suggesting that activation of AMPK might protect against ischemic vascular injury.
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Current cardiology reviews 4(3) 198-202 2008年8月 査読有りIt has been established that patients with chronic kidney disease (CKD) suffer from frequent cardiovascular events. On the other hand, recent studies suggest that renal damage tends to worsen in patients with cardiovascular diseases (CVD). Although the mechanisms for the cardiorenal association are unclear, the presence of arteriosclerotic risk factors common to both CVD and CKD is important. In arteriosclerosis, vascular derangement progresses not only in the heart but also in the kidney. In addition, heart failure, cardiac catheterization and hesitation of medical treatments due to renal dysfunction may explain the progression of renal damage. Therefore, the goal of treatments is a total control of arteriosclerotic risk factors. Medication should be selected among agents with protective effects on both heart and kidney. It is important to always consider the presence of CKD for the treatment of the cardiovascular disease and strictly control the risk factors.
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HYPERTENSION 50(4) E78-E78 2007年10月 査読有り
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Journal of the American Society of Nephrology : JASN 17(1) 113-21 2006年1月 査読有りGrowth hormone and IGF-1 have been suggested to have tissue-protective effects. Ghrelin is a stomach-derived growth hormone secretagogue. The effects of ghrelin on ischemia/reperfusion-induced renal failure in mice were examined. Ischemic acute renal failure was induced by bilateral renal artery clamping for 45 min and reperfusion for 24 h. Ghrelin (100 microg/kg mouse) or vehicle was injected subcutaneously six times before surgery and three times after surgery every 8 h. Twenty-four hours after reperfusion, the right kidney was isolated and perfused. Acetylcholine (ACh)- and adrenomedullin-induced endothelium-dependent vasorelaxation of renal vessels significantly improved in ghrelin-pretreated mice (%Delta renal perfusion pressure by 10(-7) M ACh -63.5 +/- 3.7 versus -41.2 +/- 5.5%; P < 0.05). This change was associated with significant increases of nitric oxide release in the kidneys of ghrelin-treated mice (10(-7) M ACh 35.5 +/- 5.8 versus 16.9 +/- 3.5 fmol/g kidney per min; P < 0.05). Serum concentration of urea nitrogen (53 +/- 7 versus 87 +/- 15 mg/dl; P < 0.05) and renal injury score were significantly lower in the ghrelin group (2.5 +/- 0.8 versus 5.3 +/- 1.5; P < 0.01). Tubular apoptotic index was significantly lower in the ghrelin group (5 +/- 5 versus 28 +/- 4; P < 0.05). Furthermore, the survival rate after the 60-min ischemic period was higher in the ghrelin group (80 versus 20%; P < 0.05). Ghrelin treatment significantly increased the serum level of IGF-1. However, such renal protective effects of ghrelin on ischemia/reperfusion injury were not observed in insulin receptor substrate-2 knockout mice. These results suggest that ghrelin may protect the kidneys from ischemia/reperfusion injury and that this effect is related to an improvement of endothelial function through an IGF-1-mediated pathway.
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International heart journal 46(4) 701-10 2005年7月 査読有りThe objective of the present study was to compare the effects of imidapril hydrochloride, an angiotensin converting enzyme inhibitor, and dilazep hydrochloride, an antiplatelet agent, on urinary protein excretion and renal function in patients with chronic glomerulonephritis. Imidapril (2.5 or 5 mg/day) or dilazep (300 or 450 mg/day) was administered for 3 years. Blood pressure, proteinuria, and renal function were measured before and during the treatment. In the group administered imidapril (n = 11), urinary protein decreased by approximately 50% (2.16 +/- 1.57 versus 0.90 +/- 0.53 g/g Cr, P < 0.01) and blood pressure by 14/10 mmHg (139.6 +/- 17.4/93.6 +/- 8.7 mmHg versus 122.7 +/- 10.5/81.8 +/- 9.9 mmHg, P < 0.01) and both remained at low levels during the three years of treatment. No correlation was observed between the extent of blood pressure reduction and changes in urinary protein. Serum creatinine concentrations did not change significantly (1.3 +/- 0.3 versus 1.3 +/- 0.3 mg/dL, NS). In the dilazep group (n = 12), there were no significant changes in blood pressure, urinary protein, or serum creatinine. These findings demonstrate that imidapril reduces proteinuria and contributes to preserve renal function, suggesting its usefulness in the treatment of patients with chronic glomerulonephritis.
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American journal of physiology. Heart and circulatory physiology 288(4) H1770-6-6 2005年4月 査読有りTo study the mechanisms of vascular dysfunction in diabetes mellitus, we examined the responses of the aorta to adrenomedullin (AM) and ANG II in obese Zucker (OZ), lean Zucker (LZ), and OZ rats administered fluvastatin (OZ + Flu). AM-induced endothelium-dependent vasorelaxation was impaired in OZ rats compared with LZ rats, and fluvastatin restored AM-induced, endothelium-dependent vasorelaxation (%Deltatension at 10(-7) mol/l AM; LZ, -85.1 +/- 3.1%; OZ, -50.7 +/- 2.5%; OZ + Flu, -75.6 +/- 2.7%). Expression of endothelial nitric oxide synthase (eNOS) and Akt phosphorylation in response to AM (10(-7) mol/l) were also diminished in OZ rats. Fluvastatin restored the eNOS expression and Akt phosphorylation [eNOS expression (relative intensity): LZ, 2.3 +/- 0.4; OZ, 1.0 +/- 0.2; OZ + Flu, 1.8 +/- 0.3; Akt phosphorylation (relative intensity): LZ, 2.3 +/- 0.2; OZ, 1.0 +/- 0.3; OZ + Flu, 1.9 +/- 0.2]. ANG II-induced vasoconstriction was enhanced in the aortic rings of OZ rats compared with LZ rats, and this enhanced vasoconstriction was partially normalized by fluvastatin and was abolished when the aorta of OZ rats was preincubated with the Rho kinase inhibitor Y-27632. GTPgammaS-induced contraction of permeabilized aortic smooth muscle cells, which is an indicator of the Rho-dependent Ca(2+) sensitization of contraction, was enhanced in OZ rats compared with LZ rats, and this enhanced contraction was suppressed in OZ + Flu rats. These results suggested that endothelium-dependent vasorelaxation was impaired, Ca(2+) sensitization of contraction was augmented in blood vessels of OZ rats and that fluvastatin restored vascular function by activating the Akt-dependent pathway and inhibiting the Rho-dependent pathway.
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Circulation 111(11) 1398-406 2005年3月22日 査読有りBACKGROUND: It is well known that diabetes mellitus is a major risk factor for vascular diseases such as atherosclerosis and restenosis after angioplasty. It has become clear that advanced glycation end products (AGE) and their receptor (RAGE) are implicated in vascular diseases, especially in diabetes mellitus. Nevertheless, the mechanisms by which diabetes mellitus is often associated with vascular diseases remain unclear. METHODS AND RESULTS: To study the role of endogenous cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 in the development of vascular diseases and in the expression of RAGE, we used semapimod, a pharmacological inhibitor of cytokine production, and examined its effect on neointimal formation in the femoral artery of obese Zucker (OZ) rats. We also used an adenovirus construct expressing a dominant negative mutant of the receptor for TNF-alpha (AdTNFRDeltaC) to block the action of endogenous TNF-alpha. Semapimod significantly suppressed neointimal formation and RAGE expression in OZ rats compared with untreated OZ rats. This inhibitory effect of semapimod on neointimal formation was overcome by infection of an adenovirus expressing RAGE into the femoral artery of OZ rats. Furthermore, AdTNFRDeltaC infection significantly suppressed neointimal formation and RAGE expression in the femoral artery of OZ rats. CONCLUSIONS: These results suggest that endogenous cytokines, especially TNF-alpha, were implicated in neointimal formation in OZ rats and that RAGE was a mediator of the effect of these cytokines on neointimal formation.
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Circulation 110(4) 444-51 2004年7月27日 査読有りBACKGROUND: AMP-activated protein kinase (AMPK) is a stress-activated protein kinase that works as a metabolic sensor of cellular ATP levels. Here, we investigated whether AMPK signaling has a role in the regulation of the angiotensin II (Ang II)-induced proliferation signal in rat vascular smooth muscle cells (VSMCs). METHODS AND RESULTS: Aminoimidazole-4-carboxamide-1-beta-ribofuranoside (AICAR) activated AMPK in rat VSMCs and inhibited Ang II-induced extracellular signal-regulated kinase 1/2 phosphorylation but not that of p38 MAPK or Akt/PKB. Although Ang II activated AMPK, this activation was significantly inhibited by catalase, N-acetylcysteine, and diphenyleneiodonium chloride, an NADPH oxidase inhibitor. Moreover, the observation that AMPK was activated by H2O2 suggests that AMPK is redox sensitive. The Ang II type 1 receptor antagonist valsartan but not the Ang II type 2 receptor antagonist PD123319 significantly inhibited Ang II-induced AMPK activation, suggesting that Ang II-induced AMPK activation was Ang II type 1 receptor dependent. Whereas 3H-thymidine incorporation by VSMCs treated with Ang II was significantly inhibited when the cells were pretreated with 1 mmol/L AICAR, the inhibition of AMPK by dominant-negative AMPK overexpression augmented Ang II-induced cell proliferation. Subcutaneous injection of AICAR (1 mg/g body weight per day) for 2 weeks suppressed neointimal formation after transluminal mechanical injury of the rat femoral artery. CONCLUSIONS: Our findings indicate that Ang II-induced AMPK activation is synchronized with extracellular signal-regulated kinase signaling and that AMPK works as an inhibitor of the Ang II proliferative pathway. AMPK signaling might serve as a new therapeutic target of vascular remodeling in cardiovascular diseases.
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Circulation research 95(1) 42-9 2004年7月9日 査読有りAlthough it has been established that myocyte enhancer factor 2 (MEF2) plays pivotal roles in the development of the cardiovascular system as well as skeletal muscle cells, little is known of its role in vascular inflammatory diseases such as atherosclerosis and restenosis after angioplasty. To investigate the role of MEF2 in vascular inflammation and that of p38 in the activation of MEF2, we infected cultured rat vascular smooth muscle cells (VSMCs) with an adenovirus construct expressing a dominant-negative mutant of MEF2A (MEF2ASA) or mitogen-activated protein kinase kinase 6 (MEK6AA), and examined their effects on the expression of monocyte chemoattractant protein-1 (MCP-1), which is known to play important roles in vascular inflammation. We also examined the role of MEF2 in vivo using a rat model of transluminal wire-induced injury of the femoral artery. Angiotensin II (Ang II)-induced expression of MCP-1 mRNA was significantly inhibited by infection with adenoviruses encoding MEF2ASA (AdMEF2ASA) or MEK6AA. Ang II-induced increase of MCP-1 promoter activity was also significantly suppressed by overexpression of MEF2ASA or MEK6AA. Ang II stimulated the transactivating function of MEF2A and this activation was inhibited by overexpression of MEK6AA. Infection with AdMEF2ASA suppressed MCP-1 expression in the femoral artery after the transluminal mechanical injury. AdMEF2ASA infection also inhibited macrophages infiltration and neointimal formation in the wire-injured femoral arteries. These results suggested that MEF2 activation via the p38-dependent pathway mediates vascular inflammation via stimulation of MCP-1 expression in VSMCs and macrophages infiltration.
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Circulation research 94(5) 693-700 2004年3月19日 査読有りAlthough the role of the calcineurin-dependent pathway in the development of cardiac hypertrophy has been intensively studied, little is known of its role in vascular inflammatory diseases such as atherosclerosis and restenosis after angioplasty. To help elucidate the role of calcineurin in vascular inflammation, we infected cultured vascular smooth muscle cells (VSMCs) with an adenovirus construct expressing a constitutively active mutant of calcineurin, and examined its effect on the expression of monocyte chemoattractant protein-1 (MCP-1). We also examined the role of calcineurin in vivo using a transluminal wire injury model of the rat femoral artery. Forced activation of calcineurin significantly increased the expression of MCP-1 both at the transcriptional and protein levels. Angiotensin II (Ang II) also significantly stimulated MCP-1 expression, and this increase was significantly inhibited by cyclosporin A (CyA). Constitutive activation of calcineurin stabilized MCP-1 mRNA without enhancing MCP-1 promoter activity. In accordance with the results, Ang II-induced increase of MCP-1 promoter activity was not suppressed by CyA. Ang II stabilized MCP-1 mRNA, and this effect of Ang II was diminished by CyA. CyA suppressed MCP-1 expression in the femoral artery after the transluminal mechanical injury. CyA also inhibited macrophage infiltration and neointimal formation in the wire-injured femoral arteries. These results suggested that calcineurin mediates vascular inflammation via stimulation of MCP-1 expression in VSMCs and macrophage infiltration.
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Hypertension research : official journal of the Japanese Society of Hypertension 26 Suppl S79-84-S84 2003年2月 査読有りAdrenomedullin (AM) is a potent vascular wall-derived vasorelaxing peptide which induces the release of nitric oxide (NO). To explore the role of endogenous AM in vascular function, we examined the effects of acetylcholine (ACh), AM, and AM receptor antagonists [AM (22-52), and calcitonin gene-related peptide (CGRP) (8-37)] on the isometric tension of aortic rings isolated from AM transgenic (TG) and knockout (KO) mice and wild type littermates (WT). ACh and AM caused a dose-dependent reduction of the isometric tension of aortic rings, but the degree of vasodilatation was smaller in TG than in KO or WT (% delta tension [10(-6) mol/l ACh]: KO -69 +/- 10%, WT -39 +/- 8%, TG -29 +/- 1%, p < 0.01). On the other hand, N(G)-nitro-L-arginine methyl ester, an NO synthase inhibitor, induced greater vasoconstriction in TG (% delta tension 10(-5)mol/l: KO +78 +/- 16%, WT +99 +/- 27%, TG +184 +/- 20%, p < 0.01), whereas E-4021, a cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase inhibitor, caused greater vasodilation in TG mice. Both AM antagonists increased tension in TG to a greater extent than in KO or WT mice (% delta tension [10(-6) mol/l CGRP (8-37)]: KO +24 +/- 5%, WT +51 +/- 6%, TG +75 +/- 7%, p < 0.01). Endothelial denudation of the aorta diminished the vasoconstriction caused by the AM antagonists. In conclusion, the amounts of AM expressed in the aortic endothelium influenced baseline NO release. AM antagonists increased vascular tone in WT as well as in TG, suggesting that endogenous AM plays a physiological role in the regulation of aortic tone.
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Hypertension research : official journal of the Japanese Society of Hypertension 25(5) 773-8 2002年9月 査読有りIn an attempt to find a strategy to modulate the proliferation of vascular endothelial cells, we examined whether constitutive activation of proto-oncogen protein p21 (Ras) induced the reentry of confluent human umbilical vascular endothelial cells (HUVECs) into the S phase. When an adenovirus construct expressing a constitutively active Ras mutant (Ad/RasG12V) was infected into HUVECs, their morphology changed strikingly and they appeared to be transformed. However, Ad/RasG12V-infected HUVECs did not enter the S phase, as determined by assessing 3H-thymidine incorporation. In accordance with the above results, the expression of cyclin A both at the transcript and protein levels did not increase in Ad/RasG12V-infected HUVECs relative to that in control cells, although the expression of cyclin D1 was induced in Ad/RasG12V-infected cells. Interestingly, the expression of the cyclin-dependent kinase (CDK) inhibitor p21cip1 was remarkably increased while that of p27kip1 did not decrease in Ad/RasG12V-infected HUVECs. Furthermore, CDK2 activity was not induced in Ad/RasG12V-infected HUVECs. These results suggested that the constitutive activation of Ras promoted the reentry of confluent HUVECs in the G0 phase into the G1 phase, but not into the S phase. The results also indicated that the constitutive activation of Ras might have induced the persistent expression of p21cip1 and p27kip1, and that this induction of p21cip1 and p27kip1 expression possibly caused the cell cycle arrest at the G1 phase.
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Circulation research 90(9) 1004-11 2002年5月17日 査読有り
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Circulation research 90(6) 657-63 2002年4月5日 査読有り
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Peptides 22(11) 1913-8 2001年11月 査読有りWe have reported that adrenomedullin (AM)-induced vasodilation is at least in part nitric oxide (NO)-cGMP-dependent in the rat. Although it is well known that NO is much involved in the erectile function, it is controversial as to whether AM influences the erectile function. Thus, we examined the effects of AM on intracavernous pressure (ICP) during penile erection. The left carotid artery of rats was cannulated to monitor of mean arterial pressure (MAP). Bipolar electrodes were positioned on the cavernous nerve. The right cavernous body was cannulated with a needle connected to a pressure transducer to monitor ICP. Electrical stimulation (ES) increased ICP in a voltage-dependent manner. Elevation of ICP continued during ES. The intracavernous injection of 0.5 nmol AM significantly potentiated ES-induced increases in both maximal developed ICP/MAP and area under the curve (ICP trace; AUC). Since AM slightly lowered MAP, ICP was normalized by MAP. i.v. administration of N(omega)-nitro-L-arginine, a NO synthase inhibitor, markedly decreased AM/ES-induced ICP elevation. However, in the presence of E-4021, a cGMP-specific phosphodiesterase inhibitor, AM further increased both ICP/MAP and AUC. These results suggest that a NO-cGMP pathway is involved in the regulation of AM-induced rat cavernous vasorelaxation.
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Circulation research 89(1) 63-70 2001年7月6日 査読有りTo study the mechanisms by which adrenomedullin (AM) induces endothelium-dependent vasorelaxation, we examined whether AM-induced endothelium-dependent vasodilation was mediated by the phosphatidylinositol 3-kinase (PI3K)/Akt-dependent pathway in rat aorta, because it was recently reported that PI3K/Akt was implicated in the activation of endothelial NO synthase. AM-induced vasorelaxation in thoracic aorta with intact endothelium was inhibited by pretreatment with PI3K inhibitors to the same level as that in endothelium-denuded aorta. AM elicited Akt phosphorylation in a time- and dose-dependent manner. AM-induced Akt phosphorylation was inhibited by pretreatment with a calmodulin-dependent protein kinase inhibitor as well as with PI3K inhibitors. When an adenovirus construct expressing a dominant-negative Akt mutant (Ad/dnAkt) was injected into abdominal aortas so that the mutant was expressed predominantly in the endothelium layer, AM-induced vasodilation was diminished to the same level as that in endothelium-denuded aortas. Finally, AM-induced cGMP production, which was used as an indicator for NO production, was suppressed by PI3K inhibition or by Ad/dnAkt infection into the endothelium. These results suggested that AM induced Akt activation in the endothelium via the Ca(2+)/calmodulin-dependent pathway and that this was implicated in the production of NO, which in turn induced endothelium-dependent vasodilation in rat aorta.
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The Journal of biological chemistry 276(1) 662-9 2001年1月5日 査読有りIn an attempt to examine the mechanisms by which transcriptional activity of the cyclin D1 promoter is regulated in vascular endothelial cells (EC), we examined the cis-elements in the human cyclin D1 promoter, which are required for transcriptional activation of the gene. The results of luciferase assays showed that transcriptional activity of the cyclin D1 promoter was largely mediated by SP1 sites and a cAMP-responsive element (CRE). DNA binding activity at the SP1 sites, which was analyzed by electrophoretic mobility shift assays, was significantly increased in the early to mid G(1) phase, whereas DNA binding activity at CRE did not change significantly. Furthermore, Induction of the cyclin D1 promoter activity in the early to mid G(1) phase depended largely on the promoter fragment containing the SP1 sites, whereas the proximal fragment containing CRE but not the SP1 sites was constitutively active. Finally, the increase in DNA binding and promoter activities via the SP1 sites was mediated by the Ras-dependent pathway. The results suggested that the activation of the cyclin D1 gene in vascular ECs was regulated by a dual system; one was inducible in the G(1) phase, and the other was constitutively active.
MISC
233共同研究・競争的資金等の研究課題
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日本学術振興会 科学研究費助成事業 2024年4月 - 2027年3月
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日本学術振興会 科学研究費助成事業 基盤研究(C) 2005年 - 2006年