研究者詳細 - 古橋　眞人

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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

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.

DOI

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

DOI

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

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.

DOI

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

DOI

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

DOI

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]

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

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]

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

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.

DOI

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

DOI

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

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.

DOI

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

DOI

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

DOI

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

DOI

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]

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

Significance of urinary fatty acid-binding protein 4 level as a possible biomarker for the identification of minimal change disease in patents with nephrotic-range proteinuria

Marenao Tanaka, Masato Furuhashi, Norihito Moniwa, Takuto Maeda, Hideki Takizawa, Megumi Matsumoto, Akiko Sakai, Yukimura Higashiura, Yufu Gocho, Masayuki Koyama, Yayoi Ogawa, Tetsuji Miura

BMC Nephrology ( Springer Science and Business Media {LLC} ) 21 ( 1 ) 2020年12月

Abstract Background Fatty acid-binding protein 4 (FABP4), but not FABP1 (liver-type FABP), is ectopically induced in injured glomerular endothelial cells, and urinary FABP4 (U-FABP4) level is associated with proteinuria and renal dysfunction in a general population. Methods The clinical significance of U-FABP4 was investigated in 81 patients (male/female: 43/38, age: 57 ± 17 years) who underwent kidney biopsy. Results U-FABP4 was negatively correlated with estimated glomerular filtration rate (eGFR) (r = − 0.56, P < 0.01) and was positively correlated with age, blood pressure, triglycerides, proteinuria (r = 0.58, P < 0.01), plasma FABP4 and urinary FABP1 (U-FABP1) (r = 0.52, P < 0.01). Multivariable regression analysis showed that eGFR, proteinuria and U-FABP1 were independent predictors of U-FABP4. The level of U-FABP4, but not that of proteinuria, eGFR or U-FABP1, in minimal change nephrotic syndrome (MCNS) was significantly lower than the level in membranous nephropathy (MN) and that in diabetic nephropathy. Receiver operating characteristic curve analysis indicated that U-FABP4 level ≤ 0.78 μg/gCr predicted MCNS in patients who had nephrotic-range proteinuria with a high level of accuracy. When divided by the median value of U-FABP4 at baseline in 33 of the 81 patients who could be followed up, the yearly change (post–pre) in eGFR in the low U-FABP4 group was significantly greater than that in the high U-FABP4 group (median: 11.0 vs. -5.0 mL/min/1.73m2/year). Conclusions U-FABP4 level is independently associated with proteinuria and renal dysfunction in patients with glomerular kidney disease. A low U-FABP4 level may predict MCNS in patients with nephrotic syndrome and would be a useful biomarker for differential diagnosis of MCNS and MN, which are common causes of nephrotic syndrome.

DOI

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