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
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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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
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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
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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
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MEDICINE 98(44) e17801 2019年11月 査読有り
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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
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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
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Clinical and experimental nephrology 18(5) 704-10 2014年10月 査読有り
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PloS one 9(5) e96948 2014年 査読有り
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ASAIO JOURNAL 59(3) 284-285 2013年5月 査読有り
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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
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ASAIO JOURNAL 56(4) 323-325 2010年7月 査読有り
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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
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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
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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
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International heart journal 46(4) 701-10 2005年7月 査読有り
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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
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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
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日本透析医学会雑誌 57(Suppl.1) 464-464 2024年5月
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