研究者総覧

長田 太助 (ナガタ ダイスケ)

  • 内科学講座(腎臓内科学部門) 教授
メールアドレス: nagatadjichi.ac.jp
Last Updated :2021/09/22

研究者情報

学位

  • 医学博士(東京大学)

ホームページURL

J-Global ID

プロフィール

  • 腎臓・高血圧内科専攻

研究キーワード

  • 動脈硬化   AMP kinase   PKB   apoptosis   AMPキナーゼ   低(無)酸素   アルドステロン   Akt   血管内皮細胞   循環器・高血圧   分子血管病態学   シグナル伝達   血管   低酸素   ウロテンシン   オステオポンチン   ウロコルチン   AMP   コラーゲン   キナーゼ   心臓リモデリング   血管新生   脳性ナトリウム利尿ペプチド   エンドセリン   

研究分野

  • ライフサイエンス / 循環器内科学
  • ライフサイエンス / 腎臓内科学
  • ライフサイエンス / 代謝、内分泌学

経歴

  • 2011年 - 2013年  獨協医科大学医学部准教授

研究活動情報

論文

  • Yoshiyuki Morishita, Kazuya Kubo, Yumi Haga, Atushi Miki, Kenichi Ishibashi, Eiji Kusano, Daisuke Nagata
    THERAPEUTIC APHERESIS AND DIALYSIS 18 6 612 - 617 2014年12月 [査読有り][通常論文]
     
    We evaluated the skeletal muscle loss in hemodialysis (HD) patients by bioelectrical impedance analysis (BIA) and handgrip strength test. Thirty-four HD patients and 16 healthy subjects (control group) were measured for skeletal muscle mass normalized as the skeletal muscle mass index (SMI), calculated as skeletal muscle mass (kg)/height (m)(2) using a tetrapolar bioelectrical impedance plethysmograph. Handgrip strength test was also performed using a hand dynamometer in both groups. In HD patients, the associations of SMI and handgrip strength with age, sex, HD conditions, and HD parameters such as body mass index (BMI), single-pool Kt/V (spKt/V), normalized protein catabolic rate (nPCR), creatinine generation rate (CGR) and serum albumin level (Alb) were investigated. SMI of HD patients (4.58 +/- 0.95kg/m(2)) was significantly lower than that of the control group (5.55 +/- 0.80kg/m(2), P<0.01). The handgrip strength of HD patients (19.9 +/- 7.74kg) was also significantly lower than that of the control group (33.0 +/- 8.94kg, P<0.01). In HD patients, HD duration was associated with both SMI and handgrip strength. Among HD parameters, spKt/V was negatively associated with both SMI and handgrip strength, BMI and Alb were positively associated with SMI, while nPCR and CGR were associated with neither SMI nor handgrip strength. HD duration independently contributed to skeletal muscle loss and the value of spKt/V may be affected by skeletal muscle loss in HD patients.
  • Takanori Komada, Fumitake Usui, Koumei Shirasuna, Akira Kawashima, Hiroaki Kimura, Tadayoshi Karasawa, Satoshi Nishimura, Junji Sagara, Tetsuo Noda, Shun'ichiro Taniguchi, Shigeaki Muto, Daisuke Nagata, Eiji Kusano, Masafumi Takahashi
    AMERICAN JOURNAL OF PATHOLOGY 184 5 1287 - 1298 2014年05月 [査読有り][通常論文]
     
    Inflammation plays a crucial role in the pathophysiologicat characteristics of chronic kidney disease; however, the inflammatory mechanisms underlying the chronic kidney disease process remain unclear. Recent evidence indicates that sterile inflammation triggered by tissue injury is mediated through a muttiprotein complex called the inflammasome. Therefore, we investigated the role of the inflammasome in the development of chronic kidney disease using a murine unilateral ureteral obstruction (UUO) model. Inflammasome-related molecules were up-regulated in the kidney after UUO. Apoptosis-associated speck-like protein containing a caspase recruitment domain deficiency significantly reduced inflammatory responses, such as inflammatory cell infiltration and cytokine expression, and improved subsequent renal injury and fibrosis. Furthermore, apoptosis-associated speck-like protein containing a caspase recruitment domain was specifically up-regulated in collecting duct (CD) epithelial cells of the UUO-treated kidney. In vitro experiments showed that extracellular adenosine triphosphate (ATP) induced inflammasome activation in CD epithelial cells through P2X(7)-potassium efflux and reactive oxygen species dependent pathways. These results demonstrate the molecular basis for the inflammatory response in the process of chronic kidney disease and suggest the CD inflammasome as a potential therapeutic target for preventing chronic kidney disease progression.
  • Masahiro Myojo, Daisuke Nagata, Daishi Fujita, Arihiro Kiyosue, Masao Takahashi, Hiroshi Satonaka, Yoshiyuki Morishita, Tetsu Akimoto, Ryozo Nagai, Issei Komuro, Yasunobu Hirata
    PLOS ONE 9 5 e96948  2014年05月 [査読有り][通常論文]
     
    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.
  • Yoshiyuki Morishita, Kazuya Kubo, Atushi Miki, Kenichi Ishibashi, Eiji Kusano, Daisuke Nagata
    INTERNATIONAL UROLOGY AND NEPHROLOGY 46 3 633 - 639 2014年03月 [査読有り][通常論文]
     
    To determine whether vigorous and moderate physical activity volumes are associated with skeletal muscle loss and chronic kidney disease-mineral and bone disorder (CKD-MBD) in hemodialysis (HD) patients. Skeletal muscle index (SMI) was measured using a bioelectrical impedance plethysmograph, and grip strength using a hand dynamometer, in 32 HD patients and 16 healthy controls. In HD patients, bone density was measured using digital image processing, and serum bone metabolism markers were measured as surrogate markers for CKD-MBD. Vigorous and moderate physical activity volumes of HD patients were measured using an activity monitor for 1 week, and associations between vigorous and moderate physical activity volumes and SMI, grip strength, and surrogate markers for CKD-MBD were investigated. SMI of HD patients (4.60 +/- A 0.98 kg/m(2)) was significantly lower than that of controls (5.55 +/- A 0.80 kg/m(2), p < 0.01). Grip strength of HD patients (19.9 +/- A 7.74 kg) was also significantly lower than that of controls (33.0 +/- A 8.94 kg, p < 0.01). In HD patients, vigorous and moderate physical activity volumes were significantly positively associated with SMI (beta = 0.309, p = 0.023) but not grip strength (beta = 0.231, p = 0131) after adjustment for age, sex, and HD duration. They were not associated with bone density (beta = 0.106, p = 0.470) or any markers of bone metabolism. Vigorous and moderate physical activity volumes were positively associated with skeletal muscle mass but not skeletal muscle strength or surrogate markers for CKD-MBD.
  • Yoshiyuki Morishita, Akihiko Numata, Atushi Miki, Mari Okada, Kenichi Ishibashi, Fumi Takemoto, Yasuhiro Ando, Shigeaki Muto, Daisuke Nagata, Eiji Kusano
    BMC NEPHROLOGY 15 48  2014年03月 [査読有り][通常論文]
     
    Background: The appropriate exercise counseling for chronic kidney disease (CKD) patients is crucial to improve their prognosis. There have been few studies about exercise counseling by primary care physicians for CKD patients. We investigated primary care physicians' exercise counseling practices for CKD patients and the association of these physicians' own exercise habits with exercise counseling. Methods: The population of this cross-sectional study was 3310 medical doctors who graduated from Jichi Medical University from 1978 to 2012. The study instrument was a self-administered questionnaire that was mailed in August 2012 to investigate their age class specialtynm workplace exercise habits and practices of exercise counseling for CKD. Results: 581 (64.8%) medical doctors practiced the management of CKD among a total of 933 responses. These 581 medical doctors were defined as CKD primary care physicians and their answers were analyzed. CKD primary care physicians' own exercise habits (frequencies and intensities) were as follows: frequencies: daily 71 (12.1%) >= 2-3 times/week 154 (26.5%) >= 1 time/week 146 (25.1%) and <= 1 time/month 176 (30.2%) intensities: high (>= 6 Mets) 175 (30.1%) moderate (4-6 Mets) 132 (22.7%) mild (3-4 Mets) 188 (32.3%) very mild (< 3 Mets) 47 (8.1%) and none 37 (6.4%). The CKD primary care physicians' exercise recommendation levels for CKD patients were as follows: high 31 (5.3%) moderate 176 (29.7%) low 256 (44.0%) and none 92 (15.8%). The CKD primary care physicians' exercise recommendations for CKD patients were significantly related to their own exercise frequency (p < 0.001) but they were not related to their age specialty workplace or exercise intensity. Conclusions: CKD primary care physicians' exercise recommendation level for CKD patients was limited. In addition CKD primary care physicians' own exercise habits influenced the exercise counseling for CKD patients. The establishment of guidelines for exercise by CKD patients and their dissemination among primary care physicians are needed. (University Hospital Medical Information Network Clinical Trial Registry. number UMIN000011803. Registration date Sep/19/2013)
  • Akimoto T, Yamada T, Shinoda S, Asano Y, Nagata D
    Journal of central nervous system disease 6 15 - 20 2014年 [査読有り][通常論文]
  • Yoshiyuki Morishita, Eiji Kusano, Daisuke Nagata
    Open Cardiovascular Medicine Journal 8 1 6 - 11 2014年 [査読有り][通常論文]
     
    The renin-angiotensin-aldosterone system (RAAS) blockers have been widely used in chronic kidney disease patients undergoing hemodialysis however, whether RAAS blockers have beneficial effects for cardiovascular disease in those patients has not been fully defined. This review focuses on the effects of RAAS blockers in chronic kidney disease undergoing hemodialysis for cardiovascular disease. © Morishita et al.
  • Tetsu Akimoto, Chiharu Ito, Atsushi Kotoda, Manabu Ogura, Taro Sugase, Ryuta Sato, Eiji Kusano, Daisuke Nagata
    Clinical Medicine Insights: Case Reports 6 171 - 175 2013年11月 [査読有り][通常論文]
     
    An autogenous arteriovenous fistula has been considered to be the optimal form of vascular access for hemodialysis (HD) in the field of nephrology. Nevertheless, the decision regarding the type of access, whether it be an arteriovenous fistula, an arteriovenous graft, or a central venous cath-eter, must still be individualized. In the present report, we describe the case of a female patient with advanced chronic kidney disease (CKD) associated with a hemostatic disorder. Despite the exhausted peripheral vasculature, she required recurrent platelet transfusions for severe thrombocytopenia due to aplastic anemia. The goal of care for this patient was to optimize the dialysis treatment without increasing the bleeding risk. Various concerns regarding the therapeutic conundrums encountered in the case are also discussed. © the authors, publisher and licensee Libertas Academica Limited.
  • Kiyosue A, Nagata D, Myojo M, Sato T, Takahashi M, Satonaka H, Nagai R, Hirata Y
    Hypertension research : official journal of the Japanese Society of Hypertension 34 1283 - 1287 12 2011年12月 [査読有り][通常論文]
  • Daisuke Nagata, Yasunobu Hirata
    HYPERTENSION RESEARCH 33 1 22 - 28 2010年01月 [査読有り][通常論文]
     
    It has recently been recognized that adiponectin protects the vasculature and prevents atherosclerotic change through AMP-activated protein kinase (AMPK) activation, and some of its molecular mechanisms have been clarified. AMPK, which might be a therapeutic target of metabolic abnormality, is a serine-threonine kinase, heterotrimer protein composed of three subunits of alpha, beta and gamma. It is activated by an upper kinase LKB1 and an increase in the AMP/ATP ratio. Some anabolic enzymes are directly phosphorylated and inhibited, suggesting that AMPK suppresses ATP consumption by negatively regulating the synthetic pathway. The LKB1-AMPK pathway is pivotal for controlling cellular polarity and mitosis. Furthermore, AMPK has been associated with cellular autophagy. AMPK activation could induce autophagy and prolong a period leading to cell apoptosis. Apoptosis under anoxic conditions was decreased when newly constructed, constitutively active mutants of AMPK-alpha were overexpressed in vascular endothelial cells. AMPK could inhibit the growth of vascular smooth muscle through MEK-ERK pathway inhibition. After ischemia reperfusion, dominant-negative AMPK overexpression inhibits cardiac function through the suppression of glucose uptake and fatty acid beta-oxidation in cardiac myocytes. Cardiac hypertrophy with accumulation of glycogen granules because of gene mutation of gamma 2 associated with the Wolff-Parkinson-White syndrome has been considered an activated type in most cases. It is necessary to clarify the tissue-specific and stress-specific activation mechanism of AMPK. Hypertension Research (2010) 33, 22-28; doi: 10.1038/hr.2009.187; published online 13 November 2009
  • Minoru Takaoka, Daisuke Nagata, Shinji Kihara, Iichiro Shimomura, Yu Kimura, Yasuhiko Tabata, Yoshihiko Saito, Ryozo Nagai, Masataka Sata
    CIRCULATION RESEARCH 105 9 906 - U185 2009年10月 [査読有り][通常論文]
     
    Rationale: Obesity is associated with a high incidence of cardiovascular complications. However, the molecular link between obesity and vascular disease is not fully understood. Most previous studies have focused on the association between cardiovascular disease and accumulation of visceral fat. Periadventitial fat is distributed ubiquitously around arteries throughout the body. Objective: Here, we investigated the impact of obesity on inflammation in the periadventitial adipose tissue and on lesion formation after vascular injury. Methods and Results: High-fat, high-sucrose feeding induced inflammatory changes and decreased adiponectin expression in the periadventitial adipose tissue, which was associated with enhanced neointima formation after endovascular injury. Removal of periadventitial fat markedly enhanced neointima formation after injury, which was attenuated by transplantation of subcutaneous adipose tissue from mice fed on regular chow. Adiponectin-deficient mice showed markedly enhanced lesion formation, which was reversed by local delivery, but not systemic administration, of recombinant adiponectin to the periadventitial area. The conditioned medium from subcutaneous fat attenuated increased cell number of smooth muscle cells in response to platelet derived growth factor-BB. Conclusions: Our findings suggest that periadventitial fat may protect against neointimal formation after angioplasty under physiological conditions and that inflammatory changes in the periadventitial fat may have a direct role in the pathogenesis of vascular disease accelerated by obesity. (Circ Res. 2009; 105: 906-911.)
  • Nagata D, Kiyosue A, Takahashi M, Satonaka H, Tanaka K, Sata M, Nagano T, Nagai R, Hirata Y
    Hypertension research : official journal of the Japanese Society of Hypertension 32 133 - 139 2 2009年02月 [査読有り][通常論文]
  • MW Zang, A Zuccollo, XY Hou, D Nagata, K Walsh, H Herscovitz, P Brecher, NB Ruderman, RA Cohen
    JOURNAL OF BIOLOGICAL CHEMISTRY 279 46 47898 - 47905 2004年11月 [査読有り][通常論文]
     
    The antidiabetic drug metformin stimulates AMP-activated protein kinase (AMPK) activity in the liver and in skeletal muscle. To better understand the role of AMPK in the regulation of hepatic lipids, we studied the effect of metformin on AMPK and its downstream effector, acetyl-CoA carboxylase (ACC), as well as on lipid content in cultured human hepatoma HepG2 cells. Metformin increased Thr-172 phosphorylation of the alpha subunit of AMPK in a dose- and time-dependent manner. In parallel, phosphorylation of ACC at Ser-79 was increased, which was consistent with decreasing ACC activity. Intracellular triacylglycerol and cholesterol contents were also decreased. These effects of metformin were mimicked or completely abrogated by adenoviral-mediated expression of a constitutively active AMPKalpha or a kinase-inactive AMPKalpha, respectively. An insulin-resistant state was induced by exposing cells to 30 mM glucose as indicated by decreased phosphorylation of Akt and its downstream effector, glycogen synthase kinase 3alpha/beta. Under these conditions, the phosphorylation of AMPK and ACC was also decreased, and the level of hepatocellular triacylglycerols increased. The inhibition of AMPK and the accumulation of lipids caused by high glucose concentrations were prevented either by metformin or by expressing the constitutively active AMPKalpha. The kinase-inactive AMPKalpha increased lipid content and blocked the ability of metformin to decrease lipid accumulation caused by high glucose concentrations. Taken together, these results indicate that AMPKalpha negatively regulates ACC activity and hepatic lipid content. Inhibition of AMPK may contribute to lipid accumulation induced by high concentrations of glucose associated with insulin resistance. Metformin lowers hepatic lipid content by activating AMPK, thereby mediating beneficial effects in hyperglycemia and insulin resistance.
  • D Nagata, R Takeda, M Sata, H Satonaka, E Suzuki, T Nagano, Y Hirata
    CIRCULATION 110 4 444 - 451 2004年07月 [査読有り][通常論文]
     
    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 H-3-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.
  • D Nagata, M Mogi, K Walsh
    JOURNAL OF BIOLOGICAL CHEMISTRY 278 33 31000 - 31006 2003年08月 [査読有り][通常論文]
     
    AMP-activated protein kinase (AMPK) is a stress-activated protein kinase that is regulated by hypoxia and other cellular stresses that result in diminished cellular ATP levels. Here, we investigated whether AMPK signaling in endothelial cells has a role in regulating angiogenesis. Hypoxia induced the activating phosphorylation of AMPK in human umbilical vein endothelial cells (HUVECs), and AMPK activation was required for the maintenance of pro-angiogenic Akt signaling under these conditions. Suppression of AMPK signaling inhibited both HUVEC migration to VEGF and in vitro differentiation into tube-like structures in hypoxic, but not normoxic cultures. Dominant-negative AMPK also inhibited in vivo angiogenesis in Matrigel plugs that were implanted subcutaneously in mice. These data identify AMPK signaling as a new regulator of angiogenesis that is specifically required for endothelial cell migration and differentiation under conditions of hypoxia. As such, endothelial AMPK signaling may be a critical determinant of blood vessel recruitment to tissues that are subjected to ischemic stress.
  • MH Zou, XY Hou, CM Shi, D Nagata, K Walsh, RA Cohen
    JOURNAL OF BIOLOGICAL CHEMISTRY 277 36 32552 - 32557 2002年09月 [査読有り][通常論文]
     
    Peroxynitrite (ONOO-), a nitric oxide-derived oxidant, uncouples endothelial nitric oxide synthase (eNOS) and increases enzymatic production of superoxide anions (O-2 (Zou, M. H., Shi, C., and Cohen, R. A. (2002) J. Clin. Invest. 109, 817-826). Here we studied how ONOO- influences eNOS activity. In cultured bovine aortic endothelial cells (BAEC), ONOO- increased basal and agonist-stimulated Ser(1179) phosphorylation of eNOS, whereas it decreased nitric oxide production and bioactivity. However, ONOO- strongly inhibited the phosphorylation and activity of Akt, which is known to phosphorylate eNOS-Ser(1179). Moreover, expression of an Akt dominant-negative mutant did not prevent ONOO--enhanced eNOS-Ser(1179) phosphorylation. In contrast to Akt, ONOO- significantly activated 5'-AMP-activated kinase (AMPK), as evidenced by its increased Thr(172) phosphorylation as well as increased Ser(92) phosphorylation of acetylcoenzyme A carboxylase, a downstream target of AMPK, Associated with the increased release of O-2, ONOO- significantly increased the co-immunoprecipitation of eNOS with AMPK Further, overexpression of the AMPK-constitutive active adenovirus significantly enhanced ONOO(-)up-regulated eNOS-Ser(P)(1179). In contrast, overexpression of a dominant-negative AMPK mutant attenuated the ONOO--enhanced eNOS-Ser(1179) phosphorylation as well as 07 release. We conclude that ONOO- inhibits Akt and increases AMPK-dependent Ser(1179) phosphorylation of eNOS resulting in enhanced O-2 release.

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