研究者詳細 - 伊藤　裕

論文 - 伊藤　裕

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Effect of the nonsteroidal mineralocorticoid receptor blocker, esaxerenone, on nocturnal hypertension: A post hoc analysis of the esax-htn study

Kario K., Ito S., Itoh H., Rakugi H., Okuda Y., Yoshimura M., Yamakawa S.

American Journal of Hypertension 34 （ 5 ） 540 - 551 2021年05月

ISSN 08957061

BACKGROUND Nocturnal hypertension is an important phenotype of abnormal diurnal blood pressure (BP) variability and a known risk marker for target organ damage and cardiovascular events. This study aimed to assess the differential BP-lowering effects of esaxerenone vs. eplerenone on nocturnal BP in hypertensive patients with different nocturnal dipping patterns. METHODS This was a post hoc analysis of the "Esaxerenone (CS-3150) Compared to Eplerenone in Patients with Essential Hypertension" study (NCT02890173), which was a phase 3, multicenter, randomized, controlled, double-blind, parallel-group clinical study conducted in Japan. Ambulatory BP monitoring data were collected. RESULTS Patients (n = 1,001) were randomized to esaxerenone 2.5 mg/day (n = 331) or 5 mg/day (n = 338), or eplerenone 50 mg/day (n = 332). Reductions in nighttime systolic BP (95% confidence interval) were significantly greater with 2.5 and 5 mg/day esaxerenone vs. eplerenone (-2.6 [-5.0, -0.2] and -6.4 mm Hg [-8.8, -4.0], respectively). Esaxerenone significantly reduced nighttime BP from baseline compared with eplerenone in non-dippers with previously uncontrolled BP. In addition, esaxerenone did not markedly alter nighttime BP in extreme dipper patients. In the esaxerenone 5 mg/day group, esaxerenone-induced decreases in nighttime BP were greater than eplerenone-induced decreases in older patients. CONCLUSIONS Esaxerenone may be an effective treatment option for nocturnal hypertension, especially in older patients and those with a non-dipper pattern of nocturnal BP.

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Malignancy-associated membranous nephropathy with PLA2R double-positive for glomeruli and carcinoma

Yasuda I., Tokuyama H., Hashiguchi A., Hasegawa K., Uchiyama K., Ryuzaki M., Yasuda M., Mizuno R., Ishidoya S., Wakino S., Itoh H.

Cen Case Reports 10 （ 2 ） 281 - 286 2021年05月

ISSN 2192-4449

Phospholipase A2 receptor (PLA2R) is the most common primary target antigen of idiopathic membranous nephropathy (MN) although PLA2R antibodies are also reported to be present in malignancy-associated MN. However, a case of PLA2R-positive MN secondary to PLA2R-positive carcinoma has not been reported. A 26-year-old Japanese woman presented with general fatigue, fever, and nonproductive cough. Computed tomography demonstrated a left kidney mass with pathologic diagnosis of Xp11.2 translocation renal cell carcinoma (RCC). After the second time of administration with Sunitinib, the patients exhibited significant proteinuria and hypoalbuminemia. Renal biopsy revealed a diagnosis of diffuse MN secondary to RCC. Immunofluorescence staining showed granular patterns positive for immunoglobulin (Ig) G, IgA, and C3c. PLA2R and IgG1-3 were positive, while IgG4 was negative. For the treatment of severe nephrotic syndrome, we attempted steroid therapy without any clinical improvement. Open nephrectomy was performed and surprisingly, RCC was stained for PLA2R with polarity for the basal side. At outpatient follow-up, 4 months after the operation, urinary protein had still persisted, although serum albumin was slightly increased. We report a case of PLA2R-positive MN secondary to PLA2R-positive RCC.

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Antihypertensive effects and safety of esaxerenone in patients with moderate kidney dysfunction

Ito S., Itoh H., Rakugi H., Okuda Y., Iijima S.

Hypertension Research 44 （ 5 ） 489 - 497 2021年05月

ISSN 09169636

Renin–angiotensin system inhibitors are recommended for treating hypertension with chronic kidney disease. The addition of a mineralocorticoid receptor blocker may be one option to achieve target blood pressure. We investigated the efficacy and safety of esaxerenone, a mineralocorticoid receptor blocker, in Japanese hypertensive patients with moderate kidney dysfunction. Two multicenter, open-label, nonrandomized dose escalation studies were conducted to investigate esaxerenone monotherapy and add-on therapy to renin–angiotensin system inhibitor treatment. Esaxerenone therapy was initiated at 1.25 mg/day and titrated to 2.5 and then 5 mg/day for a treatment duration of 12 weeks. Primary endpoints were changes from baseline in sitting systolic and diastolic blood pressure. Safety, pharmacokinetics, and urinary albumin-to-creatinine ratios were also assessed. Thirty-three patients received monotherapy, and 58 received add-on therapy; the mean baseline estimated glomerular filtration rates were 51.9 and 50.9 mL/min/1.73 m2, respectively. The esaxerenone dosage was increased to ≥2.5 mg/day in 100% (n = 33) and 93.1% (n = 54) of patients receiving monotherapy and add-on therapy, respectively. Reductions in sitting blood pressure from baseline to the end of treatment were similar (monotherapy: −18.5/−8.8 mmHg; add-on therapy: −17.8/−8.1 mmHg; both P < 0.001). The antihypertensive effects of esaxerenone were consistent across patient subgroups. A serum K+ level ≥5.5 mEq/L was observed in seven patients (12.1%) receiving add-on therapy but in none receiving monotherapy. All increases in serum K+ levels were transient, and no patient met predefined serum K+ level criteria for dose reduction or therapy discontinuation. No patient discontinued treatment owing to kidney function decline. Esaxerenone was effective and well tolerated in hypertensive patients with moderate kidney dysfunction.

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Effect of the Nonsteroidal Mineralocorticoid Receptor Blocker, Esaxerenone, on Nocturnal Hypertension: A <i>Post Hoc</i> Analysis of the ESAX-HTN Study

Kario, K; Ito, S; Itoh, H; Rakugi, H; Okuda, Y; Yoshimura, M; Yamakawa, S

AMERICAN JOURNAL OF HYPERTENSION 34 （ 5 ） 540 - 551 2021年05月

ISSN 0895-7061

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A CASE OF ACUTE KIDNEY INJURY CAUSED BY INTERSTITIAL NEPHRITIS COMPLICATED WITH DRESS SYNDROME

Oshima, Y; Tokuyama, H; Minakuchi, H; Wakino, S; Itoh, H

JOURNAL OF HYPERTENSION 39 E297 - E298 2021年04月

ISSN 0263-6352

ACTIVE IMMUNOTHERAPY AGAINST RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS ATTENUATES THE PROGRESSION OF DIABETIC KIDNEY DISEASE

Azegami, T; Hayashi, K; Hishikawa, A; Yoshimoto, N; Nakayama, T; Itoh, H

JOURNAL OF HYPERTENSION 39 E303 - E303 2021年04月

ISSN 0263-6352

Efficacy and safety of esaxerenone (CS-3150), a newly available nonsteroidal mineralocorticoid receptor blocker, in hypertensive patients with primary aldosteronism

Satoh F., Ito S., Itoh H., Rakugi H., Shibata H., Ichihara A., Omura M., Takahashi K., Okuda Y., Iijima S.

Hypertension Research 44 （ 4 ） 464 - 472 2021年04月

ISSN 09169636

Mineralocorticoid receptor (MR) blockers are very beneficial for patients with hypertension and primary aldosteronism (PA). We investigated the efficacy and safety of a newly available nonsteroidal MR blocker, esaxerenone, in Japanese patients with hypertension and PA. A multicenter, open-label study was conducted in Japan between October 2016 and July 2017. Patients with hypertension and PA received 12 weeks of treatment with esaxerenone, initiated at 2.5 mg/day and escalated to 5 mg/day during week 2 or 4 of treatment, based on individual response. The only other permitted antihypertensive therapies were stable dosages of a Ca2+ channel blocker or α-blocker. The primary efficacy outcome was a change in sitting systolic and diastolic blood pressure (SBP/DBP) from baseline to the end of treatment. Forty-four patients were included; dose escalation to 5 mg/day was implemented for 41 of these patients. Significant decreases in SBP and DBP were observed (point estimates [95% confidence interval] −17.7 [−20.6, −14.7] and −9.5 [−11.7, −7.3] mmHg, respectively; both p < 0.0001 at the end of treatment). Significant BP reductions were evident from week 2 and continued through to week 8; BP remained stable until week 12. The antihypertensive effect of esaxerenone on SBP was significantly greater in females and in patients receiving monotherapy. The major drug-related adverse events were serum K+ increase and estimated glomerular filtration rate decrease (both 4.5%, n = 2); no gynecomastia or breast pain was observed. We conclude that esaxerenone is a potent MR blocker with favorable efficacy and safety profiles in patients with hypertension and PA.

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EFFECT OF MINERALOCORTICOID RECEPTOR BLOCKER, ESAXERENONE, ON NOCTURNAL HYPERTENSION: A POST HOC ANALYSIS OF ESAX-HTN STUDY

Kario, K; Ito, S; Itoh, H; Rakugi, H; Okuda, Y; Yamakawa, S

JOURNAL OF HYPERTENSION 39 E374 - E374 2021年04月

ISSN 0263-6352

CLINICAL AND BIOCHEMICAL OUTCOMES AFTER RADIOFREQUENCY ABLATION FOR ALDOSTERONE-PRODUCING ADENOMA AT KEIO UNIVERSITY HOSPITAL-2020 ANNUAL REPORT

Kozuma, T; Kurihara, I; Kobayashi, S; Yokota, K; Miyashita, K; Kohata, N; Takase, K; Nakatsuka, S; Itoh, H

JOURNAL OF HYPERTENSION 39 E221 - E221 2021年04月

ISSN 0263-6352

CASZ1b is a novel transcriptional corepressor of mineralocorticoid receptor

Yokota K., Shibata H., Kurihara I., Kobayashi S., Murai-Takeda A., Itoh H.

Hypertension Research 44 （ 4 ） 407 - 416 2021年04月

ISSN 09169636

Aldosterone is a biological ligand for mineralocorticoid receptor (MR) that elevates blood pressure by promoting sodium reabsorption in the kidneys. However, the molecular mechanisms of aldosterone-MR-mediated transcription and the role of this transcription in hypertension remain largely unknown. In this study, we aimed to identify novel MR coregulators and elucidate one of the molecular mechanisms of hypertension. We purified MR-interacting factors from HEK293F cells stably expressing FLAG-MR through a biochemical approach and identified the zinc finger protein castor homolog 1 isoform b (CASZ1b) as a candidate novel MR coregulator via liquid chromatography—tandem mass spectrometry analysis. The CASZ1 gene has been implicated in hypertension in genome-wide single-nucleotide polymorphism studies, but its role in the development of hypertension remains unclear. We found that CASZ1b colocalized with MR in the kidneys and interacted with MR in an aldosterone-dependent manner. In luciferase assays using HEK293F cells, overexpression of CASZ1b reduced aldosterone-dependent MR transcriptional activity by ~50%. In contrast, knockdown of CASZ1b via RNA interference increased the expression levels of the aldosterone-induced MR target genes epithelial Na+ channel-α (ENaCα) and serum/glucocorticoid regulated kinase 1 (SGK1) by approximately twofold and 2.3-fold, respectively. Upon aldosterone-MR binding, CASZ1b interacted with MR and formed a protein complex with nucleosome remodeling deacetylase (Mi-2/NuRD), a corepressor complex with chromatin remodeling and histone deacetylation activity, which suppressed ENaCα and SGK1. These findings reveal a critical role of CASZ1b in regulating MR-mediated transcriptional activity and provide new insights into the pathophysiology of hypertension.

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BIRTH WEIGHT AND RISK FACTORS FOR ATHEROSCLEROSIS -RETROSPECTIVE COHORT STUDY IN JAPANESE WORKERS

Azegami, T; Takeda, A; Yokoyama, H; Wainai, Y; Hirose, H; Makino, S; Nishimura, T; Goto, N; Itoh, H; Mori, M

JOURNAL OF HYPERTENSION 39 E170 - E171 2021年04月

ISSN 0263-6352

ASSOCIATION OF CHILDHOOD PHYSICAL EXAMINATION AND LABORATORY PARAMETERS WITH HIGH BLOOD PRESSURE IN JAPANESE YOUNG ADULTS

Azegami, T; Uchida, K; Arima, F; Sato, Y; Awazu, M; Inokuchi, M; Takeda, A; Itoh, H; Tokumura, M; Mori, M

JOURNAL OF HYPERTENSION 39 E41 - E41 2021年04月

ISSN 0263-6352

ANTIHYPERTENSIVE EFFECTS AND SAFETY OF ESAXERENONE IN HYPERTENSIVE PATIENTS WITH MODERATE KIDNEY DYSFUNCTION

Ito, S; Itoh, H; Rakugi, H; Okuda, Y; Iijima, S

JOURNAL OF HYPERTENSION 39 E53 - E53 2021年04月

ISSN 0263-6352

ACUTE MYOCARDIAL INFARCTION AND STROKE PREVENTION WITH AMLODIPINE/ ATORVASTATIN SINGLE-PILL THERAPY FOR PATIENTS WITH HYPERTENSION AND DYSLIPIDEMIA

Nakaya, H; Sasamura, H; Saito, I; Inoue, Y; Kobayashi, M; Itoh, H

JOURNAL OF HYPERTENSION 39 E377 - E377 2021年04月

ISSN 0263-6352

RELATIONSHIP BETWEEN SERUM TOTAL BILIRUBIN CONCENTRATION AND MACROVASCULAR COMPLICATIONS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

Tanaka, M; Nishimura, T; Meguro, S; Irie, J; Saisho, Y; Mitsuishi, M; Itoh, A; Inaishi, J; Nakajima, Y; Itoh, H

JOURNAL OF HYPERTENSION 39 E208 - E208 2021年04月

ISSN 0263-6352

経過とともに増大し破裂した重複中大脳動脈分岐部動脈瘤の1例

横山邦生, 伊藤裕, 杉江亮, 山田誠, 田中秀一, 山下正真, 川西昌浩

京都医学会雑誌（(一社)京都府医師会） 68 （ 1 ） 105 - 108 2021年04月

ISSN 0453-0039

重複中大脳動脈は内頸動脈より分枝する中大脳動脈の血管奇形である。稀に重複中大脳動脈分枝部に動脈瘤が発生するがその自然歴などについてはあまり知られていない。我々は未破裂脳動脈瘤の経過で増大し破裂した重複中大脳動脈(duplicated middle cerebral artery:以下DMCA)分岐部動脈瘤の1治療例を報告する。78歳の女性が頭痛を主訴に来院された。頭部CT上、左重複中大脳動脈分岐部動脈瘤破裂によるクモ膜下出血の診断で開頭手術を行った。動脈瘤は13年前と比べ明らかに増大しネック近傍にブレブを形成していた。動脈瘤のネック確保の際、ブレブより出血をきたしたが穿通枝に注意を払いながらネッククリップを施行した。患者は術後経過に問題はなく独歩退院された。DMCA分岐部動脈瘤に対する直達手術においては術野が狭いうえ、動脈瘤頸部周囲より穿通枝が多数分枝しておりneck clippingは決して容易ではない。血管内治療の選択の余地に期待されるが今後症例の蓄積が待たれる。(著者抄録)

Importance of Adipose Tissue NAD<sup>+</sup>Biology in Regulating Metabolic Flexibility

Franczyk M.P., Qi N., Stromsdorfer K.L., Li C., Yamaguchi S., Itoh H., Yoshino M., Sasaki Y., Brookheart R.T., Finck B.N., Debosch B.J., Klein S., Yoshino J.

Endocrinology (United States) 162 （ 3 ） 2021年03月

ISSN 00137227

Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme that regulates cellular energy metabolism in many cell types. The major purpose of the present study was to test the hypothesis that NAD+ in white adipose tissue (WAT) is a regulator of whole-body metabolic flexibility in response to changes in insulin sensitivity and with respect to substrate availability and use during feeding and fasting conditions. To this end, we first evaluated the relationship between WAT NAD+ concentration and metabolic flexibility in mice and humans. We found that WAT NAD+ concentration was increased in mice after calorie restriction and exercise, 2 enhancers of metabolic flexibility. Bariatric surgery-induced 20% weight loss increased plasma adiponectin concentration, skeletal muscle insulin sensitivity, and WAT NAD+ concentration in people with obesity. We next analyzed adipocyte-specific nicotinamide phosphoribosyltransferase (Nampt) knockout (ANKO) mice, which have markedly decreased NAD+ concentrations in WAT. ANKO mice oxidized more glucose during the light period and after fasting than control mice. In contrast, the normal postprandial stimulation of glucose oxidation and suppression of fat oxidation were impaired in ANKO mice. Data obtained from RNA-sequencing of WAT suggest that loss of NAMPT increases inflammation, and impairs insulin sensitivity, glucose oxidation, lipolysis, branched-chain amino acid catabolism, and mitochondrial function in WAT, which are features of metabolic inflexibility. These results demonstrate a novel function of WAT NAMPT-mediated NAD+ biosynthesis in regulating whole-body metabolic flexibility, and provide new insights into the role of adipose tissue NAD+ biology in metabolic health.

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C-C motif chemokine receptor 9 regulates obesity-induced insulin resistance via inflammation of the small intestine in mice

Amiya T., Nakamoto N., Irie J., Taniki N., Chu P.S., Koda Y., Miyamoto K., Yamaguchi A., Shiba S., Morikawa R., Itoh H., Kanai T.

Diabetologia 64 （ 3 ） 603 - 617 2021年03月

ISSN 0012186X

Aims/hypothesis: Accumulation of adipose tissue macrophages is considered pivotal in the development of obesity-associated inflammation and insulin resistance. In addition, recent studies suggest an involvement of the intestine as the primary organ in inducing hyperglycaemia and insulin resistance. We have reported that the C-C motif chemokine receptor (CCR) CCR9 is associated with intestinal immunity and has a pathogenic role in various liver diseases. However, its contribution to type 2 diabetes is unknown. In the current study, we aimed to clarify the involvement of CCR9 in the pathology of type 2 diabetes and the potential underlying mechanisms. Methods: To elucidate how CCR9 affects the development of metabolic phenotypes, we examined the impact of CCR9 deficiency on the pathogenesis of type 2 diabetes using male C57BL/6J (wild-type [WT]) and CCR9-deficient (CCR9 knockout [KO]) mice fed a 60% high-fat diet (HFD) for 12 weeks. Results: WT and Ccr9KO mice fed an HFD exhibited a comparable weight gain; however, glucose tolerance and insulin resistance were significantly improved in Ccr9KO mice. Moreover, visceral adipose tissue (VAT) and the liver of Ccr9KO mice presented with less inflammation and increased expression of glucose metabolism-related genes than WT mice. Ccr9 and Ccl25 expression were specifically higher in the small intestine but was not altered by HFD feeding and type 2 diabetes development. Accumulation of IFN-γ-producing CD4+ T lymphocytes and increased intestinal permeability in the small intestine was observed in WT mice following HFD feeding, but these changes were suppressed in HFD-fed Ccr9KO mice. Adoptive transfer of gut-tropic CCR9-expressing T lymphocytes partially reversed the favourable glucose tolerance found in Ccr9KO mice via exacerbated inflammation in the small intestine and VAT. Conclusions/interpretation: CCR9 plays a central role in the pathogenesis of type 2 diabetes by inducing an inflammatory shift in the small intestine. Our findings support CCR9 as a new therapeutic target for type 2 diabetes via the gut–VAT–liver axis. Graphical abstract: [Figure not available: see fulltext.]

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グレリンによる内皮細胞を介した脂肪細胞の機能調節機構の解明

浦井秀徳, 伊藤裕, 神田武志

大和証券ヘルス財団研究業績集（(公財)大和証券ヘルス財団）（ 44 ） 66 - 70 2021年03月

Growth Hormone Secretagogue receptor(GHSR)欠損マウス、対照マウス、GHSR欠損ECマウス(GHSR欠損マウスで内皮細胞にのみGHSRの発現を回復させたマウス)の各3群のマウスで高脂肪食負荷を行い、内皮GHSRの脂質蓄積作用、エネルギー代謝における役割を検証した。3群のマウスに高脂肪食負荷を行ったところ、白色脂肪組織重量を増加させた。白色脂肪重量の増加と一致してGHSR欠損ECマウスでは糖代謝がGHSR欠損マウスと比較して悪化していた。培養内皮細胞では、グレリン刺激によりCd36、Ap2、Gpihbp1などの脂質取り込み遺伝子の発現の増加と遊離脂肪酸(FFA)の取り込みの増加が認められた。これらの効果はGHSR欠損マウス由来の内皮細胞では観察されなかった。siRNAによりPPARγを欠損させるとグレリンの脂質吸収作用が認められず、グレリン/GHSRシグナルが内皮PPARγを介してFFAの取り込みを促進させることを明らかにした。以上の結果から内皮GHSRがグレリンに反応して白色脂肪細胞への脂質の取り込みを増加させ白色脂肪重量および脂質代謝を調節することを明らかにした。

4）Kidney-Gut axisから見た慢性腎不全

脇野修, 松井歩, 内山清貴, 伊藤裕, 吉藤歩

日本内科学会雑誌（一般社団法人日本内科学会） 110 （ Suppl ） 93a - 93a 2021年02月

ISSN 00215384

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伊藤 裕

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論文 - 伊藤　裕