論文 - 古橋　眞人

抗リン脂質抗体症候群の腎機能障害への関与が示唆されたループス腎炎の1例

赤澤 史子, 田中 希尚, 山下 智久, 寺沢 誠, 長南 新太, 高橋 聖子, 小松 弘明, 安部 功記, 矢野 俊之, 古橋 眞人, 土橋 和文, 小川 弥生

日本腎臓学会誌 ( (一社)日本腎臓学会 )  63 ( 6-E ) 676 - 676  2021年09月

Distinct Regulation of U-ACE2 and P-ACE2 (Urinary and Plasma Angiotensin-Converting Enzyme 2) in a Japanese General Population

Masato Furuhashi, Akiko Sakai, Marenao Tanaka, Yukimura Higashiura, Kazuma Mori, Masayuki Koyama, Hirofumi Ohnishi, Shigeyuki Saitoh, Kazuaki Shimamoto

Hypertension ( Ovid Technologies (Wolters Kluwer Health) )   2021年08月

　概要を見る

Severe acute respiratory syndrome coronavirus 2 in coronavirus disease 2019 invades the host through ACE (angiotensin-converting enzyme) 2 as the host cellular receptor for a viral spike protein. ACE2 converts angiotensin II to angiotensin-(1–7) and cleaved ACE2 is detectable in urine and plasma. However, regulation of U-ACE2 (urinary ACE2) and P-ACE2 (plasma ACE2) and their alterations by renin-angiotensin-aldosterone system inhibitors remain unclear. We simultaneously investigated U-ACE2 and P-ACE2 in 605 Japanese participants (male/female: 280/325, mean age: 65±15 years) in the Tanno-Sobetsu cohort study in 2017. Males had significantly lower U-ACE2 and higher P-ACE2 than did females. There was no significant correlation between U-ACE2 and P-ACE2. P-ACE2 was significantly lower in subjects treated with renin-angiotensin-aldosterone system inhibitors than in those not treated with renin-angiotensin-aldosterone system inhibitors, but there was no significant difference in U-ACE2 between the groups. Multivariable regression analyses showed that female sex, high levels of systolic blood pressure, hemoglobin A1c, and urinary albumin-to-creatinine ratio, and low uric acid level were independent predictors of high U-ACE2 level and that high levels of γ-glutamyl transpeptidase, estimated glomerular filtration rate, and uric acid were independent predictors of high P-ACE2 level. In conclusion, U-ACE2 and P-ACE2 are distinctly regulated and the use of renin-angiotensin-aldosterone system inhibitors is not an independent predictor of their levels in a Japanese general population. U-ACE2 is associated with high blood pressure, high glucose level, and microalbuminuria, and low urate level, whereas P-ACE2 is associated with liver dysfunction, high glomerular filtration rate, and high urate level.

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Independent Association of Fatty Liver Index With Left Ventricular Diastolic Dysfunction in Subjects Without Medication

Masato Furuhashi, Atsuko Muranaka, Satoshi Yuda, Marenao Tanaka, Masayuki Koyama, Mina Kawamukai-Nishida, Satoko Takahashi, Yukimura Higashiura, Daisuke Miyamori, Ryo Nishikawa, Hirofumi Ohnishi, Shigeyuki Saitoh, Kazuaki Shimamoto, Tetsuji Miura

The American Journal of Cardiology ( Elsevier BV )   2021年08月

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Elevated Fatty Liver Index Is Independently Associated With New Onset of Hypertension During a 10‐Year Period in Both Male and Female Subjects

Yukimura Higashiura, Masato Furuhashi, Marenao Tanaka, Satoko Takahashi, Kazuma Mori, Daisuke Miyamori, Masayuki Koyama, Hirofumi Ohnishi, Norihito Moniwa, Keita Numata, Takashi Hisasue, Nagisa Hanawa, Tetsuji Miura

Journal of the American Heart Association ( Ovid Technologies (Wolters Kluwer Health) )  10 ( 14 )  2021年07月

　概要を見る

Background Fatty liver index (FLI), a predictor of nonalcoholic fatty liver disease, has been reported to be associated with several metabolic disorders. Because of a sex difference in FLI level, we hypothesized that FLI is associated with development of hypertension to a greater extent in men or women. Methods and Results We investigated the relationship between FLI and development of hypertension during a 10‐year period in a general population of subjects who received annual health examinations (n=28 990). After exclusion (44.9%) of subjects with missing data and those with hypertension at baseline, a total of 15 965 subjects (men/women: 9466/6499) were included. FLI level was significantly higher in men than in women. During the 10‐year period, 2304 men (24.3%) and 745 women (11.5%) had new onset of hypertension. Multivariable Cox proportional hazard models with a restricted cubic spline showed that the hazard ratios (HRs) for development of hypertension after adjustment of age, systolic blood pressure, estimated glomerular filtration rate, habits of smoking and alcohol drinking, family history of hypertension, and diagnosis of diabetes mellitus and dyslipidemia increased gradually with increase in FLI in men and increased rapidly and then slowly with increase in FLI in women. There was a significant interaction between FLI and sex for the risk of hypertension in all of the subjects ( P =0.049). The addition of FLI to traditional risk factors significantly improved the discriminatory capability. Conclusions A high level of FLI predicts the development of hypertension in both men and women, although distribution patterns of HRs were different between sexes.

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Seasonal variation of serum 25-hydroxyvitamin D level in hemodialysis patients in the northernmost island of Japan

Yufu Gocho, Marenao Tanaka, Hirohito Sugawara, Masato Furuhashi, Norihito Moniwa, Tomohisa Yamashita, Hideki Takizawa, Hiroya Mukai, Kouhei Ohno, Takuto Maeda, Arata Osanami, Hirofumi Ohnishi, Hiroaki Komatsu, Kazuma Mori, Tetsuji Miura

Clinical and Experimental Nephrology ( Springer Science and Business Media {LLC} )   2021年07月

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Involvement of necroptosis in contrast-induced nephropathy in a rat CKD model

Satoru Shibata, Norihito Moniwa, Atsushi Kuno, Ayumu Kimura, Wataru Ohwada, Hirohito Sugawara, Yufu Gocho, Marenao Tanaka, Toshiyuki Yano, Masato Furuhashi, Masaya Tanno, Takayuki Miki, Tetsuji Miura

Clinical and Experimental Nephrology ( Springer Science and Business Media {LLC} )  25 ( 7 ) 708 - 717  2021年07月  [国内誌]

　概要を見る

BACKGROUND: The risk of contrast-induced nephropathy (CIN) is high in patients with chronic kidney disease (CKD). However, the mechanism of CIN in CKD is not fully understood. Here, we prepared a clinically relevant model of CIN and examined the role of necroptosis, which potentially cross-talks with autophagy, in CIN. METHODS: In Sprague-Dawley rats, CKD was induced by subtotal nephrectomy (SNx, 5/6 nephrectomy) 4 weeks before induction of CIN. CIN was induced by administration of a contrast medium (CM), iohexol, following administration of indomethacin and N-omega-Nitro-L-arginine methyl ester. Renal function and tissue injuries were assessed 48 h after CM injection. RESULTS: Serum creatinine (s-Cre) and BUN were increased from 0.28 ± 0.01 to 0.52 ± 0.02 mg/dl and from 15.1 ± 0.7 to 29.2 ± 1.2 mg/dl, respectively, after SNx alone. CM further increased s-Cre and BUN to 0.69 ± 0.03 and 37.2 ± 2.1, respectively. In the renal tissue after CM injection, protein levels of receptor-interacting serine/threonine-protein kinase (RIP) 1, RIP3, cleaved caspase 3, and caspase 8 were increased by 64 ~ 212%, while there was reduction in LC3-II and accumulation of p62. Necrostatin-1, an RIP1 inhibitor, administered before and 24 h after CM injection significantly suppressed elevation of s-Cre, BUN and urinary albumin levels, kidney injury molecule-1 expression and infiltration of CD68-positive macrophages in renal tissues after CM injection. CONCLUSION: The results suggest that necroptosis of proximal tubular cells contributes to CIN in CKD and that suppression of protective autophagy by pro-necroptotic signaling may also be involved.

DOI PubMed

Screening of the Drug-Induced Effects of Prostaglandin EP2 and FP Agonists on 3D Cultures of Dexamethasone-Treated Human Trabecular Meshwork Cells

Megumi Watanabe, Yosuke Ida, Masato Furuhashi, Yuri Tsugeno, Hiroshi Ohguro, Fumihito Hikage

Biomedicines    2021年07月

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Independent association of plasma xanthine oxidoreductase activity with hypertension in nondiabetic subjects not using medication

Masato Furuhashi, Yukimura Higashiura, Masayuki Koyama, Marenao Tanaka, Takayo Murase, Takashi Nakamura, Seigo Akari, Akiko Sakai, Kazuma Mori, Hirofumi Ohnishi, Shigeyuki Saitoh, Kazuaki Shimamoto, Tetsuji Miura

Hypertension Research ( Springer Science and Business Media {LLC} )  44 ( 9 ) 1213 - 1220  2021年06月  [国際誌]

　概要を見る

Xanthine oxidoreductase (XOR), a rate-limiting and catalyzing enzyme of uric acid formation in purine metabolism, is involved in reactive oxygen species generation. Plasma XOR activity has been shown to be a novel metabolic biomarker related to obesity, liver dysfunction, hyperuricemia, dyslipidemia, and insulin resistance. However, the association between plasma XOR activity and hypertension has not been fully elucidated. We investigated the association of hypertension with plasma XOR activity in 271 nondiabetic subjects (male/female: 119/152) who had not taken any medications in the Tanno-Sobetsu Study, a population-based cohort. Males had higher plasma XOR activity than females. Plasma XOR activity was positively correlated with mean arterial pressure (r = 0.128, P = 0.036). When the subjects were divided by the presence and absence of hypertension into an HT group (male/female: 34/40) and a non-HT group (male/female: 85/112), plasma XOR activity in the HT group was significantly higher than that in the non-HT group (median: 39 vs. 28 pmol/h/mL, P = 0.028). There was no significant difference in uric acid levels between the two groups. Multivariable logistic regression analysis showed that plasma XOR activity (odds ratio: 1.091 [95% confidence interval: 1.023-1.177] per 10 pmol/h/mL, P = 0.007) was an independent determinant of the risk for hypertension after adjustment for age, sex, current smoking and alcohol consumption, estimated glomerular filtration rate, brain natriuretic peptide, and insulin resistance index. The interaction of sex with plasma XOR activity was not significant for the risk of hypertension. In conclusion, plasma XOR activity is independently associated with hypertension in nondiabetic individuals who are not taking any medications.

DOI PubMed

CKDモデルの造影剤腎症におけるネクロプトーシスの役割

柴田 智, 茂庭 仁人, 木村 歩, 後町 結, 田中 希尚, 古橋 眞人, 三浦 哲嗣

日本腎臓学会誌 ( (一社)日本腎臓学会 )  63 ( 4 ) 447 - 447  2021年06月

CKD発症予測におけるfatty liver indexの意義

高橋 聖子, 田中 希尚, 古橋 眞人, 長南 新太, 宮森 大輔, 後町 結, 塙 なぎさ, 茂庭 仁人, 大西 浩文, 三浦 哲嗣

日本腎臓学会誌 ( (一社)日本腎臓学会 )  63 ( 4 ) 453 - 453  2021年06月

血液透析患者におけるビタミンDの季節変動に関する検討

田中 希尚, 後町 結, 菅原 浩仁, 茂庭 仁人, 山下 智久, 古橋 眞人, 滝沢 英毅, 向 博也, 大野 紘平, 三浦 哲嗣

日本透析医学会雑誌 ( (一社)日本透析医学会 )  54 ( Suppl.1 ) 379 - 379  2021年05月

Antiatherosclerotic Phenotype of Perivascular Adipose Tissue Surrounding the Saphenous Vein in Coronary Artery Bypass Grafting

Takuma Mikami, Masato Furuhashi, Akiko Sakai, Ryosuke Numaguchi, Ryo Harada, Syuichi Naraoka, Takeshi Kamada, Yukimura Higashiura, Marenao Tanaka, Shunsuke Ohori, Taku Sakurada, Masanori Nakamura, Yutaka Iba, Joji Fukada, Tetsuji Miura, Nobuyoshi Kawaharada

Journal of the American Heart Association ( Ovid Technologies (Wolters Kluwer Health) )  10 ( 7 ) OJ32 - 2  2021年04月

　概要を見る

Background Perivascular adipose tissue (PVAT) is associated with metabolically driven chronic inflammation called metaflammation, which contributes to vascular function and the pathogenesis of vascular disease. The saphenous vein (SV) is commonly used as an essential conduit in coronary artery bypass grafting, but the long‐term patency of SV grafts is a crucial issue. The use of the novel “no‐touch” technique of SV harvesting together with its surrounding tissue has been reported to result in good long‑term graft patency of SV grafts. Herein, we investigated whether PVAT surrounding the SV (SV‐PVAT) has distinct phenotypes compared with other PVATs of vessels. Methods and Results Fat pads were sampled from 48 patients (male/female, 32/16; age, 72±8 years) with coronary artery disease who underwent elective coronary artery bypass grafting. Adipocyte size in SV‐PVAT was significantly larger than the sizes in PVATs surrounding the internal thoracic artery, coronary artery, and aorta. SV‐PVAT and PVAT surrounding the internal thoracic artery had smaller extents of fibrosis, decreased gene expression levels of fibrosis‐related markers, and less metaflammation, as indicated by a significantly smaller extent of cluster of differentiation 11c–positive M1 macrophage infiltration, higher gene expression level of adiponectin, and lower gene expression levels of inflammatory cytokines, than did PVATs surrounding the coronary artery and aorta. Expression patterns of adipocyte developmental and pattern‐forming genes were totally different among the PVATs of the vessels. Conclusions The phenotype of SV‐PVAT, which may result from inherent differences in adipocytes, is closer to that of PVAT surrounding the internal thoracic artery than that of PVAT surrounding the coronary artery or that of PVAT surrounding the aorta. SV‐PVAT has less metaflammation and consecutive adipose tissue remodeling, which may contribute to high long‐term patency of grafting when the no‐touch technique of SV harvesting is used.

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Impact of atrial fibrillation on the risk of ischemic stroke in patients on hemodialysis: BOREAS-HD3 Study

Ayumu Kimura, Marenao Tanaka, Norihito Moniwa, Arata Osanami, Koki Abe, Daisuke Miyamori, Yufu Gocho, Satoru Shibata, Makoto Terasawa, Yusuke Okazaki, Tomohisa Yamashita, Masayuki Koyama, Masato Furuhashi, Hirofumi Ohnishi, Tetsuji Miura

Clinical and Experimental Nephrology ( Springer Science and Business Media {LLC} )  25 ( 3 ) 297 - 304  2021年03月

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血中FABP4濃度の上昇からみた一般集団における心血管死の予測 12年間の前向き研究(Elevated Circulating FABP4 Concentration Predicts Cardiovascular Death in a General Population: A 12-year Prospective Study)

齋藤 礼衣, 古橋 眞人, 小山 雅之, 東浦 幸村, 赤坂 憲, 田中 希尚, 茂庭 仁人, 大西 浩文, 齋藤 重幸, 浦 信行, 島本 和明, 三浦 哲嗣

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  85回   OJ16 - 4  2021年03月

Fatty acid-binding protein 4 is an independent factor in the pathogenesis of retinal vein occlusion

Fumihito Hikage, Masato Furuhashi, Yosuke Ida, Hiroshi Ohguro, Megumi Watanabe, Soma Suzuki, Kaku Itoh

PLOS ONE ( Public Library of Science ({PLoS}) )  16 ( 1 )  2021年01月

　概要を見る

The main objective of current study was to identify the fatty acid-binding protein 4 (FABP4) expressed in both adipocytes and macrophages in vitreous fluid from patients with retinal vein occlusion (RVO). Patients with RVO (n = 14, CRVO; central RVO n = 5, BRVO; branch RVO n = 9) and non-RVO (macular hole or epiretinal membrane, n = 18) were surgically treated by a 25 or 27G vitrectomy. Undiluted vitreous fluid samples obtained as the result of surgery were subjected to enzyme-linked immunosorbent assays to measure the levels of FABP4 and vascular endothelial growth factor A (VEGFA).Data including ocular blood flow by laser speckle flow graphy (LSFG), height and weight, systemic blood pressures and several blood biochemistry values were collected. Among the LSFG mean blur rate (MBR) values of the optic nerve head (ONH) at baseline, MA (MBR of all area), MV (MBR of the vascular area), and MV-MT (MBR of the tissue area) were significantly decreased in patients with CRVO. The levels of V-FABP4 and V-VEGFA were relatively or significantly (P< 0.05) higher in the BRVO or CRVO patients compared to the non-RVO patients, respectively. A positive correlation (r = 0.36, P = 0.045) or a negative correlation (r = -0.51, P = 0.006) was observed between Log V-FABP4 and Log V-VEGF, or Log V-FABP4 and MV-MT at post-operative 1-week, respectively. Furthermore, neither of these factors were affected with respect to sex, body mass index and several clinical parameters that were collected, except that a positive correlation was observed for Log V-FABP4 with blood urea nitrogen. Stepwise multivariable regression analyses indicated that MV-MT at post-operative 1week was independently associated with Log V-FABP4 after adjustment for age and gender, and gender and Log V-FABP4 were independently associated with Log V-VEGFA after adjustment for age. The findings reported herein suggest that an independent factor, FABP4 may be synergistically involved in the pathogenesis of RVO with VEGFA.

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Prediction of new onset of diabetes mellitus during a 10-year period by using a combination of levels of alanine aminotransferase and γ-glutamyl transferase

Daisuke Miyamori, Marenao Tanaka, Masato Furuhashi, Hirofumi Ohnishi, Masayuki Koyama, Arata Osanami, Yukimura Higashiura, Keita Numata, Takashi Hisasue, Nagisa Hanawa, Norihito Moniwa, Tetsuji Miura

Endocrine Journal ( Japan Endocrine Society )   2021年

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A Resuscitated Case of Acute Myocardial Infarction with both Familial Hypercholesterolemia Phenotype Caused by Possibly Oligogenic Variants of the <i>PCSK9</i> and <i>ABCG5</i> Genes and Type I CD36 Deficiency

Ryo Nishikawa, Masato Furuhashi, Mika Hori, Masatsune Ogura, Mariko Harada-Shiba, Takeshi Okada, Masahiro Koseki, Takeshi Kujiraoka, Hiroaki Hattori, Ryosuke Ito, Atsuko Muranaka, Nobuaki Kokubu, Tetsuji Miura

Journal of Atherosclerosis and Thrombosis ( Japan Atherosclerosis Society )   2021年  [国内誌]

　概要を見る

A 56-year-old postmenopausal woman with out-of-hospital cardiac arrest caused by acute myocardial infraction was successfully resuscitated by intensive treatments and recovered without any neurological disability. She was diagnosed as having familial hypercholesterolemia (FH) based on a markedly elevated low-density lipoprotein cholesterol (LDL-C) level and family history of premature coronary artery disease. Genetic testing in her family members showed that a variant of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene (c.2004C＞A, p.S668R), which had been previously reported as having uncertain significance, was associated with FH, indicating that the variant is a potential candidate for the FH phenotype. Next-generation sequencing analysis for the proband also showed that there was a heterozygous mutation of the ATP-binding cassette sub-family G member 5 (ABCG5) gene (c.1166G＞A, R389H), which has been reported to increase LDL-C level and the risk of cardiovascular disease. She was also diagnosed as having type 1 CD36 deficiency based on a lack of myocardial uptake of 123 I-labeled 15-(p-iodophenyl)-3-R,S-methyl-pentadecanoic acid in scintigraphy and the absence of CD36 antigen in both monocytes and platelets in flow cytometry. She had a homozygous mutation of the CD36 gene (c.1126-5_1127delTTTAGAT), which occurs in a canonical splice site (acceptor) and is predicted to disrupt or distort the normal gene product. To our knowledge, this is the first report of a heterozygous FH phenotype caused by possibly oligogenic variants of the PCSK9 and ABCG5 genes complicated with type I CD36 deficiency caused by a novel homozygous mutation. Both FH phenotype and CD36 deficiency might have caused extensive atherosclerosis, leading to acute myocardial infarction in the present case.

DOI PubMed

Circulating PCSK7 Level is Independently Associated with Obesity, Triglycerides Level and Fatty Liver Index in a General Population without Medication

Masato Furuhashi, Yu Kataoka, Ryo Nishikawa, Masayuki Koyama, Akiko Sakai, Yukimura Higashiura, Marenao Tanaka, Shigeyuki Saitoh, Kazuaki Shimamoto, Hirofumi Ohnishi

Journal of Atherosclerosis and Thrombosis ( Japan Atherosclerosis Society )   2021年

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Prediction and validation of nonalcoholic fatty liver disease by fatty liver index in a Japanese population

Satoko Takahashi, Marenao Tanaka, Yukimura Higashiura, Kazuma Mori, Nagisa Hanawa, Hirofumi Ohnishi, Masato Furuhashi

Endocrine Journal ( Japan Endocrine Society )   2021年

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Treatment with anagliptin, a DPP-4 inhibitor, decreases FABP4 concentration in patients with type 2 diabetes mellitus at a high risk for cardiovascular disease who are receiving statin therapy

Masato Furuhashi, Ichiro Sakuma, Takeshi Morimoto, Yukimura Higashiura, Akiko Sakai, Megumi Matsumoto, Mio Sakuma, Michio Shimabukuro, Takashi Nomiyama, Osamu Arasaki, Koichi Node, Shinichiro Ueda

Cardiovascular Diabetology ( Springer Science and Business Media {LLC} )  19 ( 1 )  2020年12月

　概要を見る

Abstract Background Fatty acid-binding protein 4 (FABP4) acts as a novel adipokine, and elevated FABP4 concentration is associated with obesity, insulin resistance and atherosclerosis. Dipeptidyl peptidase-4 (DPP-4) inhibitors, a class of antidiabetic drugs, have distinct structures among the drugs, possibly leading to a drug class effect and each drug effect. Sitagliptin, a DPP-4 inhibitor, has been reported to decrease FABP4 concentration in drug-naïve and sulfonylurea-treated patients with type 2 diabetes mellitus. Anagliptin, another DPP-4 inhibitor, was shown to decrease low-density lipoprotein cholesterol (LDL-C) level to a greater extent than that by sitagliptin in the Randomized Evaluation of Anagliptin vs. Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. Aim and methods As a sub-analysis study using data obtained from the REASON trial, we investigated the effects of treatment with anagliptin (n = 148, male/female: 89/59) and treatment with sitagliptin (n = 159, male/female: 93/66) for 52 weeks on FABP4 concentration in patients with type 2 diabetes mellitus at a high risk for cardiovascular events who were receiving statin therapy. Results The DPP-4 inhibitor had been administered in 82% of the patients in the anagliptin group and 81% of the patients in sitagliptin group prior to randomization. Serum FABP4 level was significantly decreased by 7.9% by treatment with anagliptin (P = 0.049) and was not significantly decreased by treatment with sitagliptin (P = 0.660). Change in FABP4 level was independently associated with basal FABP4 level and changes in waist circumference and creatinine after adjustment of age, sex and the treatment group. Conclusion Anagliptin decreases serum FABP4 concentration independent of change in hemoglobin A1c or LDL-C in patients with type 2 diabetes mellitus and dyslipidemia who are on statin therapy. Trial registration ClinicalTrials.gov number NCT02330406. Registered January 5, 2015, https://clinicaltrials.gov/ct2/show/NCT02330406

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