Papers - ITOH Hiroshi

FCoR-Foxo1 Axis Regulates α-Cell Mass through Repression of Arx Expression.

Noriko Kodani, Jun Nakae, Masaki Kobayashi, Osamu Kikuchi, Tadahiro Kitamura, Hiroshi Itoh

iScience 23 ( 1 ) 100798 - 100798 2020.01

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Pancreatic endocrine cell development into differentiated α- and β-cells is highly regulated and involves multiple transcription factors. However, the mechanisms behind the determination of α- and β-cell masses remains unclear. We previously identified Foxo1 CoRepressor (FCoR), which inhibits Foxo1 by acetylation. Here we demonstrate that Fcor-knockout mice (FcorKO) exhibit significantly increased α-cell mass, expression of the master α-cell regulatory transcription factor Aristaless-related homeobox (Arx), which can be normalized by β-cell-specific FCoR overexpression (FcorKO-βFcor), and exhibit β-to-α-cell conversion. Compared with FcorKO, β-cell-specific Foxo1 knockout in the FcorKO (DKO) led to decreased Arx expression and α-cell mass. Foxo1 binding to Arx promoter led to DNA methyltransferase 3a (Dnmt3a) dissociation, Arx promoter hypomethylation, and increased Arx expression. In contrast, FCoR suppressed Arx through Foxo1 inhibition and Dnmt3a recruitment to Arx promoter and increased Arx promoter methylation. Our findings suggest that the FCoR-Foxo1 axis regulates pancreatic α-cell mass by suppressing Arx expression.

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Association of glomerular DNA damage and DNA methylation with one-year eGFR decline in IgA nephropathy.

Kaori Hayashi, Akihito Hishikawa, Akinori Hashiguchi, Tatsuhiko Azegami, Norifumi Yoshimoto, Ran Nakamichi, Hirobumi Tokuyama, Hiroshi Itoh

Scientific reports 10 ( 1 ) 237 - 237 2020.01

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Accumulation of DNA double-strand breaks (DSBs) is linked to aging and age-related diseases. We recently reported the possible association of DNA DSBs with altered DNA methylation in murine models of kidney disease. However, DSBs and DNA methylation in human kidneys was not adequately investigated. This study was a cross-sectional observational study to evaluate the glomerular DNA DSB marker γH2AX and phosphorylated Ataxia Telangiectasia Mutated (pATM), and the DNA methylation marker 5-methyl cytosine (5mC) by immunostaining, and investigated the association with pathological features and clinical parameters in 29 patients with IgA nephropathy. To evaluate podocyte DSBs, quantitative long-distance PCR of the nephrin gene using laser-microdissected glomerular samples and immunofluorescent double-staining with WT1 and γH2AX were performed. Glomerular γH2AX level was associated with glomerular DNA methylation level in IgA nephropathy. Podocytopathic features were associated with increased number of WT1(+)γH2AX(+) cells and reduced amount of PCR product of the nephrin gene, which indicate podocyte DNA DSBs. Glomerular γH2AX and 5mC levels were significantly associated with the slope of eGFR decline over one year in IgA nephropathy patients using multiple regression analysis adjusted for age, baseline eGFR, amount of proteinuria at biopsy and immunosuppressive therapy after biopsy. Glomerular γH2AX level was associated with DNA methylation level, both of which may be a good predictor of renal outcome in IgA nephropathy.

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Double-Blind Randomized Phase 3 Study Comparing Esaxerenone (CS-3150) and Eplerenone in Patients With Essential Hypertension (ESAX-HTN Study).

Sadayoshi Ito, Hiroshi Itoh, Hiromi Rakugi, Yasuyuki Okuda, Motonobu Yoshimura, Satoru Yamakawa

Hypertension (Dallas, Tex. : 1979) 75 ( 1 ) 51 - 58 2020.01

Accepted,  ISSN  0194-911X

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Mineralocorticoid receptors (MRs) are implicated in the pathology of hypertension. MR blockers are recommended for the treatment of salt-sensitive or resistant hypertension. However, use of currently available MR blockers is limited by adverse events. This phase 3 multicenter, randomized, double-blind study compared the efficacy and safety of esaxerenone, a new selective nonsteroidal MR blocker, at 2.5 and 5 mg/day and eplerenone 50 mg/day in Japanese patients with essential hypertension. After a 4-week washout period, 1001 eligible adults with hypertension were randomized evenly to esaxerenone 2.5 or 5 mg/day or eplerenone 50 mg/day treatments, taken orally once daily for 12 weeks. Primary end points were changes in sitting systolic or diastolic blood pressure (BP) from baseline at the end of treatment. Esaxerenone 2.5 mg/day was noninferior to eplerenone for reductions in sitting and 24-hour BP. Reductions in BP with esaxerenone 5 mg/day were significantly greater than those with esaxerenone 2.5 mg/day. Changes in diurnal BP showed persistent 24-hour antihypertensive effects in all treatment groups. The proportions of patients achieving target sitting BP (<140/90 mm Hg) were 31.5%, 41.2%, and 27.5% with esaxerenone 2.5 and 5 mg/day and eplerenone 50 mg/day, respectively. Incidences of adverse events (all mild or moderate) were similar across treatment groups. These results indicate that esaxerenone is an effective and well-tolerated MR blocker in Japanese patients with essential hypertension, with BP-lowering activity at least equivalent to eplerenone. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT02890173.

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Historical changes and between-facility differences in adrenal venous sampling for primary aldosteronism in Japan.

Yuichi Fujii, Yoshiyu Takeda, Isao Kurihara, Hiroshi Itoh, Takuyuki Katabami, Takamasa Ichijo, Norio Wada, Yui Shibayama, Takanobu Yoshimoto, Yoshihiro Ogawa, Junji Kawashima, Masakatsu Sone, Nobuya Inagaki, Katsutoshi Takahashi, Minemori Watanabe, Yuichi Matsuda, Hiroki Kobayashi, Hirotaka Shibata, Kohei Kamemura, Michio Otsuki, Koichi Yamamto, Atsushi Ogo, Toshihiko Yanase, Shintaro Okamura, Shozo Miyauchi, Megumi Fujita, Tomoko Suzuki, Hironobu Umakoshi, Tatsuki Ogasawara, Mika Tsuiki, Mitsuhide Naruse

Journal of human hypertension 34 ( 1 ) 34 - 42 2020.01

Accepted,  ISSN  0950-9240

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Primary aldosteronism (PA) is a common curable cause of hypertension. Adrenal venous sampling (AVS) is recommended for subtype diagnosis but is a difficult procedure. Recently, an increased prevalence of PA was reported, creating a greater demand for treatment of the condition in clinical facilities. The aim of the present study was to identify the historical changes over time and the differences between facilities in the success rate and subtype diagnosis of PA. The database of the PA registry developed by the Japan PA Study (JPAS) was used. A total of 2599 patients with PA who underwent AVS were evaluated. The overall success rate of AVS was 88%. The bilateral subtype was the dominant subtype, comprising 69% of cases. During the period 2004-2011 to 2011-2017, there were significant changes in the total number of AVS procedures (from 562 to 1732), ratio of ACTH administration with AVS (75 to 97%), success rate (79 to 90%), and proportion with bilateral subtype diagnosis (53 to 72%). There were also significant inter-facility differences in the number of AVS procedures (6 to 322), success rate (59 to 97%), and proportion with the bilateral subtype (44 to 86%). The principal enrolled department was Endocrinology (86%), and the ratio of unilateral PA was significantly higher in this department than in others (32% vs. 25%). In conclusion, the number of AVS procedures performed, the success rate, and the proportion with the bilateral subtype increased over time after normalizing the centre difference. Significant differences were observed between the centres.

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【スルスルわかる 糖尿病と腸内細菌の関係】糖尿病と腸内細菌 がんと腸内細菌

竹林 駿太, 入江 潤一郎, 伊藤 裕

糖尿病ケア ((株)メディカ出版)  17 ( 1 ) 40 - 41 2020.01

Accepted,  ISSN  1348-9968

【スルスルわかる 糖尿病と腸内細菌の関係】糖尿病と腸内細菌 腸腎連関と腸内細菌

入江 潤一郎, 伊藤 裕

糖尿病ケア ((株)メディカ出版)  17 ( 1 ) 37 - 39 2020.01

Accepted,  ISSN  1348-9968

Maternal gut microbiota in pregnancy influences offspring metabolic phenotype in mice

• Kimura I*, Miyamoto J, Ohue-Kitano R, Watanabe K, Yamada T, Onuki M, Aoki R, Isobe Y, Kashihara D, Inoue D, Inaba A, Takamura Y, Taira S, Kumaki S, Watanabe M, Ito M, Nakagawa F, Irie J, Kakuta H, Shinohara M, Iwatsuki K, Tsujimoto G, Ohno H, Arita M, Itoh H, Hase K

Science 367 ( 6481 ) 8429 2020

Accepted,  ISSN  0036-8075

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Foxo in T Cells Regulates Thermogenic Program through Ccr4/Ccl22 Axis.

Tetsuhiro Kikuchi, Jun Nakae, Yoshinaga Kawano, Nobuyuki Watanabe, Masafumi Onodera, Hiroshi Itoh

iScience 22   81 - 96 2019.12

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Crosstalk between immunity and the thermogenic program has provided insight into metabolic energy regulation. Here, we generated thermogenic program-accelerating mice (T-QKO), in which Foxo1 is knockout and Foxo3 is hetero-knockout in CD4+ T cells. T-QKO exhibit lean phenotype under HFD due to increased energy expenditure. Cold exposure significantly increased expression of the thermogenic genes (Ppargc1a and Ucp1), Th2 cytokines (Il4 and Il13), and Th2 marker gene (Gata3) in subcutaneous adipose tissue (SC) of T-QKO. Furthermore, Ccr4 expression was significantly increased in Th2 cells of T-QKO, and cold exposure induced Ccl22 expression in SC, leading to increased accumulation of Th2 cell population in SC of T-QKO. These data reveal a mechanism by which cold exposure induces selective recruitment of Th2 cells into SC, leading to regulation of energy expenditure by generating beige adipocyte and suggest that inhibition of Foxo in T cells may support a strategy to prevent and treat obesity.

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Home-based Aerobic Exercise and Resistance Training in Peritoneal Dialysis Patients: A Randomized Controlled Trial

Uchiyama K., Washida N., Morimoto K., Muraoka K., Kasai T., Yamaki K., Miyashita K., Wakino S., Itoh H.

Scientific Reports (Scientific Reports)  9 ( 1 )  2019.12

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© 2019, The Author(s). Potential effects of aerobic and resistance training in peritoneal dialysis (PD) patients have been partially elucidated. We investigated effects of a home-based exercise program on physical functioning and health-related quality of life (HRQOL) in PD patients. Patients were randomly assigned to exercise (n = 24) and usual care (n = 23) groups. The exercise patients performed aerobic exercise thrice weekly and resistance training twice weekly at home for 12 weeks. The usual care patients received no specific intervention. The distance in incremental shuttle walking test significantly improved in the exercise group compared with the usual care group (P = 0.02). Among the HRQOL subscales assessed using the Kidney Disease Quality of Life-Short Form questionnaire, kidney disease component summary (P = 0.03), physical role functioning (P = 0.01), emotional role functioning (P < 0.01), and role/social component summary (P < 0.01) significantly improved in the exercise group. Moreover, serum albumin was significantly maintained in the exercise group (P = 0.03). There were no reported adverse events associated with the intervention. To our knowledge, this is the first randomized controlled trial to indicate the beneficial effects of a 12-week home-based exercise program exclusively in PD patients.

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Induction of human pluripotent stem cells into kidney tissues by synthetic mRNAs encoding transcription factors

Hiratsuka K., Monkawa T., Akiyama T., Nakatake Y., Oda M., Goparaju S., Kimura H., Chikazawa-Nohtomi N., Sato S., Ishiguro K., Yamaguchi S., Suzuki S., Morizane R., Ko S., Itoh H., Ko M.

Scientific Reports (Scientific Reports)  9 ( 1 )  2019.12

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© 2019, The Author(s). The derivation of kidney tissues from human pluripotent stem cells (hPSCs) and its application for replacement therapy in end-stage renal disease have been widely discussed. Here we report that consecutive transfections of two sets of synthetic mRNAs encoding transcription factors can induce rapid and efficient differentiation of hPSCs into kidney tissues, termed induced nephron-like organoids (iNephLOs). The first set - FIGLA, PITX2, ASCL1 and TFAP2C, differentiated hPSCs into SIX2 + SALL1 + nephron progenitor cells with 92% efficiency within 2 days. Subsequently, the second set - HNF1A, GATA3, GATA1 and EMX2, differentiated these cells into PAX8 + LHX1 + pretubular aggregates in another 2 days. Further culture in both 2-dimensional and 3-dimensional conditions produced iNephLOs containing cells characterized as podocytes, proximal tubules, and distal tubules in an additional 10 days. Global gene expression profiles showed similarities between iNephLOs and the human adult kidney, suggesting possible uses of iNephLOs as in vitro models for kidneys.

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Long-term phase 3 study of esaxerenone as mono or combination therapy with other antihypertensive drugs in patients with essential hypertension.

Hiromi Rakugi, Sadayoshi Ito, Hiroshi Itoh, Yasuyuki Okuda, Satoru Yamakawa

Hypertension research : official journal of the Japanese Society of Hypertension 42 ( 12 ) 1932 - 1941 2019.12

Accepted,  ISSN  0916-9636

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This study investigated the long-term antihypertensive effects of esaxerenone, a novel nonsteroidal mineralocorticoid receptor blocker, alone or in combination with a calcium channel blocker (CCB) or a renin-angiotensin system (RAS) inhibitor, in Japanese patients with essential hypertension. Patients were treated with esaxerenone starting at 2.5 mg/day increasing to 5 mg/day if required to achieve blood pressure (BP) targets as a monotherapy or with a CCB or RAS inhibitor. After the first 12 weeks of treatment, an additional antihypertensive agent could be added if required to achieve the target BP; the total treatment period was 28 or 52 weeks. The primary endpoint was a change from baseline in sitting BP. Of the 368 enrolled patients, 245 received monotherapy, and 59 and 64, respectively, took a CCB or RAS inhibitor concurrently. Mean changes from baseline in sitting systolic/diastolic BP (95% confidence intervals) at weeks 12, 28 and 52 were -16.1 (-17.3, -14.9)/-7.7 (-8.4, -6.9), -18.9 (-20.2, -17.7)/-9.9 (-10.7, -9.2), and -23.1 (-25.0, -21.1)/-12.5 (-13.6, -11.3) mmHg, respectively (all P < 0.0001 vs baseline). Similar BP reductions at these weeks were observed between all patient subgroups stratified by age, and the observed decreases in 24-h ambulatory BP were consistent with the efficacy observed in sitting BP. Esaxerenone was also well-tolerated with a rate of hyperkalemia at 5.4% (serum potassium ≥5.5 mEq/L), indicating a good safety profile for treatment over the long-term or in combination with a CCB or RAS inhibitor. In conclusion, esaxerenone may be a promising treatment option for patients with hypertension.

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Ketone body receptor GPR43 regulates lipid metabolism under ketogenic conditions.

Miyamoto J, Ohue-Kitano R, Mukouyama H, Nishida A, Watanabe K, Igarashi M, Irie J, Tsujimoto G, Satoh-Asahara N, Itoh H, Kimura I

Proceedings of the National Academy of Sciences of the United States of America 116 ( 47 ) 23813 - 23821 2019.11

ISSN  0027-8424

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Xanthine oxidase inhibitor ameliorates postischemic renal injury in mice by promoting resynthesis of adenine nucleotides.

Kentaro Fujii, Akiko Kubo, Kazutoshi Miyashita, Masaaki Sato, Aika Hagiwara, Hiroyuki Inoue, Masaki Ryuzaki, Masanori Tamaki, Takako Hishiki, Noriyo Hayakawa, Yasuaki Kabe, Hiroshi Itoh, Makoto Suematsu

JCI insight 4 ( 22 )  2019.11

Accepted

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Although oxidative stress plays central roles in postischemic renal injury, region-specific alterations in energy and redox metabolism caused by short-duration ischemia remain unknown. Imaging mass spectrometry enabled us to reveal spatial heterogeneity of energy and redox metabolites in the postischemic murine kidney. After 10-minute ischemia and 24-hour reperfusion (10mIR), in the cortex and outer stripes of the outer medulla, ATP substantially decreased, but not in the inner stripes of the outer medulla and inner medulla. 10mIR caused renal injury with elevation of fractional excretion of sodium, although histological damage by oxidative stress was limited. Ischemia-induced NADH elevation in the cortex indicated prolonged production of reactive oxygen species by xanthine oxidase (XOD). However, consumption of reduced glutathione after reperfusion suggested the amelioration of oxidative stress. An XOD inhibitor, febuxostat, which blocks the degradation pathway of adenine nucleotides, promoted ATP recovery and exerted renoprotective effects in the postischemic kidney. Because effects of febuxostat were canceled by silencing of the hypoxanthine phosphoribosyl transferase 1 gene in cultured tubular cells, mechanisms for the renoprotective effects appear to involve the purine salvage pathway, which uses hypoxanthine to resynthesize adenine nucleotides, including ATP. These findings suggest a novel therapeutic approach for acute ischemia/reperfusion renal injury with febuxostat through salvaging high-energy adenine nucleotides.

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Predictors of Clinical Success After Surgery for Primary Aldosteronism in the Japanese Nationwide Cohort.

Mitsuha Morisaki, Isao Kurihara, Hiroshi Itoh, Mitsuhide Naruse, Yoshiyu Takeda, Takuyuki Katabami, Takamasa Ichijo, Norio Wada, Takanobu Yoshimoto, Yoshihiro Ogawa, Masakatsu Sone, Mika Tsuiki, Hirotaka Shibata, Junji Kawashima, Megumi Fujita, Minemori Watanabe, Yuichi Matsuda, Hiroki Kobayashi, Tomoko Suzuki

Journal of the Endocrine Society 3 ( 11 ) 2012 - 2022 2019.11

Accepted

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Context: Aldosterone-producing adenomas are a curable subtype of primary aldosteronism (PA); however, hypertension persists in some patients after adrenalectomy. Objective: To identify factors associated with, and develop prediction models for, blood pressure (BP) normalization or improvement after adrenalectomy. Design: Retrospective analysis of patients treated between 2006 and 2018, with a 6-month follow-up. Setting: A nationwide, 29-center Japanese registry encompassing 15 university hospitals and 14 city hospitals. Patients: We categorized 574 participants in the Japan Primary Aldosteronism Study, who were diagnosed with PA and underwent adrenalectomy, as BP normalized or improved, on the basis of their presentations at 6 months postsurgery. Main Outcome Measure: The rate of complete, partial, and absent clinical success. Predictive factors related to BP outcomes after PA surgery were also evaluated. Results: Complete clinical success was achieved in 32.6% and partial clinical success was achieved in 53.0% of the patients at 6 months postsurgery. The following five variables were independent predictors for BP normalization: ≤7 years of hypertension, body mass index ≤25 kg/m2, no more than one antihypertensive medication, absence of medical history of diabetes, and female sex. The area under the receiver operator characteristic curve was 0.797 in the BP normalization model. Conclusion: We established models that predicted postoperative BP normalization in patients with PA. These should be useful for shared decision-making regarding adrenalectomy for PA.

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Application of Japanese guidelines for gestational weight gain to multiple pregnancy outcomes and its optimal range in 101,336 Japanese women

Nomura K, Nagashima K, Suzuki S, Itoh H

Scientific Reports 9 ( 1 ) 17310 2019.11

Accepted

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Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men.

Irie J, Inagaki E, Fujita M, Nakaya H, Mitsuishi M, Yamaguchi S, Yamashita K, Shigaki S, Ono T, Yukioka H, Okano H, Nabeshima YI, Imai SI, Yasui M, Tsubota K, Itoh H

Endocrine journal 67 ( 2 ) 153 - 160 2019.11

Accepted,  ISSN  0918-8959

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GLP-1受容体作動薬により過食の軽減が認められた2型糖尿病合併高度肥満症の一例

後藤 伸子, 入江 潤一郎, 清水 真美子, 喜田 素子, 伊藤 裕

肥満研究 ((一社)日本肥満学会)  25 ( Suppl. ) 310 - 310 2019.10

Accepted,  ISSN  1343-229X

原発性アルドステロン症における腎障害は心血管イベントと異なり血中アルドステロン値と直接相関する

曽根 正勝, 川島 彰透, 稲垣 暢也, 武田 仁勇, 伊藤 裕, 栗原 勲, 一城 貴政, 方波見 卓行, 和田 典男, 小川 佳宏, 宮内 省蔵, 鈴木 知子, 成瀬 光栄, JPAS and JRAS Study gruop

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)  42回   263 - 263 2019.10

社会環境の変化により、嗜好が変化した肥満症の一例

清水 真美子, 入江 潤一郎, 後藤 伸子, 喜田 素子, 伊藤 裕

肥満研究 ((一社)日本肥満学会)  25 ( Suppl. ) 251 - 251 2019.10

Accepted,  ISSN  1343-229X

肺高血圧を合併し心不全をきたした高度肥満症の一例

喜田 素子, 入江 潤一郎, 後藤 伸子, 倉田 英明, 伊藤 裕

肥満研究 ((一社)日本肥満学会)  25 ( Suppl. ) 310 - 310 2019.10

Accepted,  ISSN  1343-229X