論文 - 古橋　眞人

慢性腎臓病研究の進歩から見えてきた高血圧成因 慢性腎臓病の新規治療ターゲットとしての異所性FABP4発現の可能性

古橋 眞人, 田中 希尚, 三浦 哲嗣

日本高血圧学会総会プログラム・抄録集 ( (NPO)日本高血圧学会 )  40回   255 - 255  2017年10月

Ectopic Fatty Acid-Binding Protein 4 Expression in the Vascular Endothelium is Involved in Neointima Formation After Vascular Injury

Takahiro Fuseya, Masato Furuhashi, Megumi Matsumoto, Yuki Watanabe, Kyoko Hoshina, Tomohiro Mita, Shutaro Ishimura, Marenao Tanaka, Tetsuji Miura

JOURNAL OF THE AMERICAN HEART ASSOCIATION ( WILEY )  6 ( 9 )  2017年09月  [査読有り]

　概要を見る

Background-Fatty acid-binding protein 4 (FABP4) is expressed in adipocytes, macrophages, and endothelial cells of capillaries but not arteries. FABP4 is secreted from adipocytes in association with lipolysis, and an elevated circulating FABP4 level is associated with obesity, insulin resistance, and atherosclerosis. However, little is known about the link between FABP4 and endovascular injury. We investigated the involvement of ectopic FABP4 expression in endothelial cells in neointima hyperplasia after vascular injury. Methods and Results-Femoral arteries of 8-week-old male mice were subjected to wire-induced vascular injury. After 4 weeks, immunofluorescence staining showed that FABP4 was ectopically expressed in endothelial cells of the hyperplastic neointima. Neointima formation determined by intima area and intima to media ratio was significantly decreased in FABP4-defficient mice compared with that in wild-type mice. Adenovirus-mediated overexpression of FABP4 in human coronary artery endothelial cells (HCAECs) in vitro increased inflammatory cytokines and decreased phosphorylation of nitric oxide synthase 3. Furthermore, FABP4 was secreted from HCAECs. Treatment of human coronary smooth muscle cells or HCAECs with the conditioned medium of Fabp4-overexpressed HCAECs or recombinant FABP4 significantly increased gene expression of inflammatory cytokines and proliferationand adhesion-related molecules in cells, promoted cell proliferation and migration of human coronary smooth muscle cells, and decreased phosphorylation of nitric oxide synthase 3 in HCAECs, which were attenuated in the presence of an anti-FABP4 antibody. Conclusions-Ectopic expression and secretion of FABP4 in vascular endothelial cells contribute to neointima formation after vascular injury. Suppression of ectopic FABP4 in the vascular endothelium would be a novel strategy against post-angioplasty vascular restenosis.

DOI

ベバシズマブにより糸球体内皮障害と高度蛋白尿を呈し薬剤中止とARBにて軽快した一例

木村 幸滋, 山下 智久, 田中 希尚, 茂庭 仁人, 古橋 眞人, 小川 弥生, 三浦 哲嗣

日本腎臓学会誌 ( (一社)日本腎臓学会 )  59 ( 6 ) 915 - 915  2017年09月

良性小脳髄膜腫による水頭症を合併し、術後に完全寛解に至った膜性腎症の一例

森 和真, 山下 智久, 安部 功記, 木村 幸滋, 田中 希尚, 茂庭 仁人, 古橋 眞人, 小川 弥生, 三浦 哲嗣

日本腎臓学会誌 ( (一社)日本腎臓学会 )  59 ( 6 ) 882 - 882  2017年09月

高度腎機能障害で発症したが自然軽快したTINU症候群の一例

小川 俊史, 山下 智久, 田中 希尚, 茂庭 仁人, 古橋 眞人, 小川 弥生, 三浦 哲嗣

日本腎臓学会誌 ( (一社)日本腎臓学会 )  59 ( 6 ) 895 - 895  2017年09月

本態性血小板血症に続発した軽鎖沈着症による末期腎不全の一例

安部 功記, 茂庭 仁人, 山下 智久, 田中 希尚, 古橋 眞人, 村瀬 和幸, 池田 博, 杉田 真太朗, 黒田 せつ子, 小川 弥生, 三浦 哲嗣

日本腎臓学会誌 ( (一社)日本腎臓学会 )  59 ( 6 ) 893 - 893  2017年09月

肺高血圧症に伴うCKDの特徴

茂庭 仁人, 山下 智久, 田中 希尚, 古橋 眞人, 永野 伸卓, 西田 絢一, 村中 敦子, 國分 宣明, 藤戸 健史, 望月 敦史, 永原 大五, 橋本 暁佳, 三浦 哲嗣

日本腎臓学会誌 ( (一社)日本腎臓学会 )  59 ( 3 ) 362 - 362  2017年04月

非糖尿病かつ検尿異常のない場合もLDL-コレステロール120mg/dL以上はCKD-ステージG3への進展の危険因子となる

山下 智久, 松本 環, 大西 浩文, 塙 なぎさ, 田中 希尚, 茂庭 仁人, 古橋 眞人, 三浦 哲嗣

日本腎臓学会誌 ( (一社)日本腎臓学会 )  59 ( 3 ) 372 - 372  2017年04月

急性心不全における急性腎障害予測スコアにフロセミド静注量は必要か?

柴田 智, 山下 智久, 田中 希尚, 茂庭 仁人, 古橋 眞人, 三浦 哲嗣

日本腎臓学会誌 ( (一社)日本腎臓学会 )  59 ( 3 ) 374 - 374  2017年04月

SGLT2阻害薬カナグリフロジン投与による脂肪酸結合タンパク4(FABP4)濃度の経時的変化とその規定因子の検討

古橋 眞人, 松本 めぐみ, 平光 伸也, 田中 希尚, 茂庭 仁人, 石井 潤一, 三浦 哲嗣

糖尿病 ( (一社)日本糖尿病学会 )  60 ( Suppl.1 ) S - 361  2017年04月

多腺性自己免疫症候群3A型に房室ブロックを合併した一例 抗Ro/SS-A抗体との関連

中田 圭, 矢野 俊之, 大島 洸人, 古橋 眞人, 丹野 雅也, 斎藤 重幸, 三木 隆幸, 三浦 哲嗣

糖尿病 ( (一社)日本糖尿病学会 )  60 ( Suppl.1 ) S - 452  2017年04月

Serum FABP5 concentration is a potential biomarker for residual risk of atherosclerosis in relation to cholesterol efflux from macrophages

Masato Furuhashi, Masatsune Ogura, Megumi Matsumoto, Satoshi Yuda, Atsuko Muranaka, Mina Kawamukai, Akina Omori, Marenao Tanaka, Norihito Moniwa, Hirofumi Ohnishi, Shigeyuki Saitoh, Mariko Harada-Shiba, Kazuaki Shimamoto, Tetsuji Miura

SCIENTIFIC REPORTS ( NATURE PUBLISHING GROUP )  7 ( 1 ) 217  2017年03月  [査読有り]

　概要を見る

Cholesterol efflux capacity (CEC) from macrophages, the first step in the reverse cholesterol transport pathway, is inversely associated with residual risk for atherosclerotic cardiovascular disease. Fatty acid-binding protein 4 (FABP4) and FABP5 are expressed in both adipocytes and macrophages and play significant roles in the development of insulin resistance and atherosclerosis. Both FABP4 and FABP5 are secreted from cells, and their circulating levels are associated with insulin resistance and atherosclerosis. We investigated the association between CEC and levels of FABP4 and FABP5 in 250 subjects without any medications. CEC was positively correlated with HDL cholesterol level and negatively correlated with concentrations of high-sensitivity C-reactive protein (hsCRP) and FABP5, but not FABP4. Multiple regression analysis demonstrated that FABP5 concentration was an independent predictor of CEC after adjustment of age, gender and levels of HDL cholesterol and hsCRP. In 129 of the 250 subjects who underwent carotid ultrasonography, mean intima-media thickness was negatively correlated with CEC and was positively correlated with concentrations of FABP4 and FABP5. In conclusion, in contrast to FABP4, circulating FABP5 is associated with decreased CEC and carotid atherosclerosis, suggesting that FABP5 level is a regulatory factor of CEC and a potential biomarker for residual risk of atherosclerosis.

DOI PubMed

Impact of the Number of Anti-Thrombosis Agents in Hemodialysis Patients: BOREAS-HD2 Study

Marenao Tanaka, Norihito Moniwa, Hirofumi Ohnishi, Tomohisa Yamashita, Masayuki Koyama, Yufu Gocho, Keitaro Nishizawa, Yukishige Kimura, Hirohito Sugawara, Sayaka Murakami, Yusuke Okazaki, Masato Furuhashi, Hideaki Yoshida, Tetsuji Miura

KIDNEY & BLOOD PRESSURE RESEARCH ( KARGER )  42 ( 3 ) 553 - 564  2017年  [査読有り]

　概要を見る

Background/Aims: Relationships between the number of anti-thrombosis agents, clinical benefits and adverse events in hemodialysis (HD) patients are unclear. Methods: All patients on HD in 22 institutes (n = 1,071) were enrolled and followed up for 3 years. After exclusion of patients with missing data, kidney transplantation or retraction of consent during the follow-up period (n = 204), mortality rate and ischemic and hemorrhagic events were compared between different regimens of anti-thrombosis agents. Results: The use of dual or triple antiplatelet (AP) agents (HR:2.03, 95% CI:1.01-4.13, p = 0.04) and the combination of an AP agent and warfarin (WF) (HR:4.84, 95% CI 1.96-11.96, p < 0.001) were associated with an increase in hemorrhagic events compared with no use of anti-thrombosis agents. No anti-thrombosis regimen was associated with a significant change in risk of ischemic stroke. The use of dual or triple AP agents, but not WF, was associated with an increase in cardiovascular mortality (HR:2.48, 95% CI:1.24-4.76, p = 0.01). Conclusion: A significant increase in hemorrhagic events by the use of dual or more AP agents and by co-administration of an AP agent and WF in patients on HD should be considered in planning their anti-thrombosis regimen. (C) 2017 The Author(s) Published by S. Karger AG, Basel

DOI PubMed

Transcriptome and Metabolome Analyses in Exogenous FABP4-and FABP5-Treated Adipose-Derived Stem Cells

Tokunori Yamamoto, Masato Furuhashi, Takeshi Sugaya, Tsuyoshi Oikawa, Megumi Matsumoto, Yasuhito Funahashi, Yoshihisa Matsukawa, Momokazu Gotoh, Tetsuji Miura

PLOS ONE ( PUBLIC LIBRARY SCIENCE )  11 ( 12 ) e0167825  2016年12月  [査読有り]

　概要を見る

Adipose-derived stem cells (ADSC), which exist near adipocytes in adipose tissue, have been used as a potential tool of regenerative medicine. Lipid chaperones, fatty acid-binding protein 4 (FABP4) and 5 (FABP5), are abundantly expressed in adipocytes. FABP4 has recently been shown to be secreted from adipocytes during lipolysis in a non-classical pathway and may act as an adipokine. Here, we investigated the role of exogenous FABP4 and FABP5 in transcriptional and metabolic regulation in ADSC. FABP4 and FABP5 were little expressed in ADSC. However, both FABP4 and FABP5 were significantly induced after adipocyte differentiation of ADSC and were secreted from the differentiated adipocytes. Analysis of microarray data, including gene ontology enrichment analysis and cascade analysis of the protein-protein interaction network using a transcription factor binding site search, demonstrated that treatment of ADSC with FABP4 or FABP5 affected several kinds of genes related to inflammatory and metabolic responses and the process of cell differentiation. Notably, myogenic factors, including myocyte enhancer factors, myogenic differentiation 1 and myogenin, were modulated by treatment of ADSC with FABP4, indicating that exogenous FABP4 treatment is partially associated with myogenesis in ADSC. Metabolome analysis showed that treatment of ADSC with FABP4 and with FABP5 similarly, but differently in extent, promoted hydrolysis and/or uptake of lipids, consequentially together with enhancement of beta oxidation, inhibition of downstream of the glycolysis pathway, accumulation of amino acids, reduction of nucleic acid components and increase in the ratio of reduced and oxidized nicotinamide adenine dinucleotide phosphates (NADPH/NADP(+)), an indicator of reducing power, and the ratio of adenosine triphosphate and adenosine monophosphate (ATP/AMP), an indicator of the energy state, in ADSC. In conclusion, secreted FABP4 and FABP5 from adipocytes as adipokines differentially affect transcriptional and metabolic regulation in ADSC near adipocytes. The adiposity condition in the host of regenerative medicine may affect characteristics of ADSC by exposure of the balance of FABP4 and FABP5.

DOI PubMed

糖尿病性腎症による末期腎不全に至ってから診断されたCushing病の1例

高橋 遼, 舘越 勇輝, 茂庭 仁人, 西田 絢一, 矢野 俊之, 古橋 眞人, 三木 隆幸, 三浦 哲嗣

日本内分泌学会雑誌 ( (一社)日本内分泌学会 )  92 ( S.Branc ) 13 - 13  2016年12月

2型糖尿病患者においてipragliflozinは他のSGLT2阻害薬と比較し降圧効果に優れる

茂庭 仁人, 山下 智久, 田中 希尚, 古橋 眞人, 三浦 哲嗣

日本高血圧学会総会プログラム・抄録集 ( (NPO)日本高血圧学会 )  39回   350 - 350  2016年09月

造影剤腎症、薬剤性急性間質性腎炎との鑑別に難渋したコレステロール塞栓症の一例

西沢 慶太郎, 山下 智久, 田中 希尚, 茂庭 仁人, 古橋 眞人, 野口 寛子, 三浦 哲嗣

日本腎臓学会誌 ( (一社)日本腎臓学会 )  58 ( 6 ) 820 - 820  2016年08月

Transplantation associated-thrombotic microangiopathy(TA-TMA)の二例

安部 功記, 山下 智久, 田中 希尚, 茂庭 仁人, 古橋 眞人, 小川 弥生, 三浦 哲嗣

日本腎臓学会誌 ( (一社)日本腎臓学会 )  58 ( 6 ) 767 - 767  2016年08月

Independent Link Between Levels of Proprotein Convertase Subtilisin/Kexin Type 9 and FABP4 in a General Population Without Medication.

Masato Furuhashi, Akina Omori, Megumi Matsumoto, Yu Kataoka, Marenao Tanaka, Norihito Moniwa, Hirofumi Ohnishi, Hideaki Yoshida, Shigeyuki Saitoh, Kazuaki Shimamoto, Tetsuji Miura

The American journal of cardiology   118 ( 2 ) 198 - 203  2016年07月  [査読有り]  [国際誌]

　概要を見る

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to and degrades the low-density lipoprotein (LDL) receptor, leading to hypercholesterolemia and cardiovascular risk. Fatty acid binding protein 4 (FABP4/adipocyte FABP/aP2) is secreted from adipocytes in association with lipolysis, and circulating FABP4 has been reported to act as an adipokine for the development of insulin resistance and atherosclerosis. Elevated serum FABP4 level is associated with obesity, insulin resistance, dyslipidemia, and atherosclerosis. In this study, we examined the association between circulating levels of FABP4 and PCSK9 in a general population. A total of 265 subjects (male/female: 98/167) who were not on medication were recruited from subjects of the Tanno-Sobetsu Study, and concentrations of FABP4 and PCSK9 were measured. The level of FABP4, but not that of PCSK9, showed a gender difference, being higher in women than in men. FABP4 level was independently associated with gender, adiposity, renal dysfunction, and levels of cholesterol and PCSK9. There was a significant and gender-different correlation between PCSK9 level and age: negatively in men (r = -0.250, p = 0.013) and positively in women (r = 0.183, p = 0.018). After adjustment of age, gender, and LDL cholesterol level, PCSK9 level was positively and independently correlated with FABP4 concentration. In conclusion, PCSK9 level is differentially regulated by gender during aging. Circulating FABP4 is independently associated with the PCSK9 level, suggesting that elevation of FABP4 level as an adipokine leads to dyslipidemia through increased PCSK9 level and subsequent degradation of the LDL receptor.

DOI PubMed

Impact of use of angiotensin II receptor blocker on all-cause mortality in hemodialysis patients: prospective cohort study using a propensity-score analysis.

Marenao Tanaka, Tomohisa Yamashita, Masayuki Koyama, Norihito Moniwa, Kohei Ohno, Kaneto Mitsumata, Takahito Itoh, Masato Furuhashi, Hirofumi Ohnishi, Hideaki Yoshida, Kazufumi Tsuchihashi, Tetsuji Miura

Clinical and experimental nephrology   20 ( 3 ) 469 - 78  2016年06月  [査読有り]  [国内誌]

　概要を見る

BACKGROUND: It is controversial whether treatment with an angiotensin II receptor blocker (ARB) or a calcium channel blocker (CCB) improves prognosis of hemodialysis (HD) patients. METHODS: This study was designed as a multicenter prospective cohort study. HD patients (n = 1071) were enrolled from 22 institutes in January 2009 and followed up for 3 years. Patients with missing data, kidney transplantation or retraction of consent during the follow-up period (n = 204) were excluded, and 867 patients contributed to analysis of mortality. Propensity score (PS) for use of ARB and that for CCB was calculated using a multiple logistic regression model. RESULTS: ARB and CCB were prescribed in 45.6 and 54.7 % of patients at enrollment. During the 3-year follow-up period, all-cause mortality and cardiovascular mortality rates were 18.8 and 5.1 %, respectively. Kaplan-Meier curves showed that all-cause and cardiovascular mortality rates were lower in the ARB group than in the non-ARB group, though the mortality rates were similar in the CCB group and non-CCB group. In PS-stratified Cox regression analysis, ARB treatment was associated with 34 and 45 % reduction of all-cause death and cardiovascular death, respectively. In PS matching analysis, ARB treatment was associated with a significant reduction (46 % reduction) in the risk of all-cause death. A significant impact of CCB treatment on all-cause or cardiovascular mortality was not detected in PS analysis. CONCLUSIONS: The use of an ARB, but not a CCB, is associated with reduced all-cause and cardiovascular mortalities in patients on HD.

DOI PubMed