研究者詳細 - 伊藤　裕

論文 - 伊藤　裕

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Epidermal growth factor receptor/extracellular signal-regulated kinase pathway enhances mineralocorticoid receptor transcriptional activity through protein stabilization

Mitsuishi Y., Shibata H., Kurihara I., Kobayashi S., Yokota K., Murai-Takeda A., Hayashi T., Jo R., Nakamura T., Morisaki M., Itoh H.

Molecular and Cellular Endocrinology （Molecular and Cellular Endocrinology） 473 89 - 99 2018年09月

ISSN 03037207

© 2018 Elsevier B.V. Activation of mineralocorticoid receptor (MR) is evoked by aldosterone, and it induces hypertension and cardiovascular disease when it's concomitant with excessive salt loading. We have proposed the notion of “MR-associated hypertension” in which add-on therapy of MR blockers is effective even though serum aldosterone level is within normal range. To elucidate its underlying molecular mechanism, we focused on the effect of epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (ERK) activation on MR activity. Epidermal growth factor (EGF) administration increased MR transcriptional activity through EGFR/ERK pathway and increased protein level by counteracting MR ubiquitylation in vitro. EGF administration in vivo also increased MR protein level and target gene expression in kidney, which were decreased by EGFR inhibitor. In addition, the administration of EGFR inhibitor lowered systolic blood pressure and MR activity in DOCA/salt-treated mice. In conclusion, EGFR/ERK pathway activation is considered as one of the underlying mechanisms of aberrant MR activation and EGFR/ERK pathway blockade could be an alternative approach for the prevention of MR-related cardiovascular events.

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Difference of seasonal variation between glycated albumin and glycated haemoglobin

Tanaka K., Meguro S., Tanaka M., Irie J., Saisho Y., Itoh H.

Annals of Clinical Biochemistry （Annals of Clinical Biochemistry） 55 （ 5 ） 583 - 587 2018年09月

ISSN 00045632

© The Author(s) 2018. Background: Glycated albumin reflects 2–3-week glycaemic controls, and in addition to glycated haemoglobin, it has been used as a glycaemic control indicator. We presumed that glycated albumin also has seasonal variations and is related to temperature, similar to glycated haemoglobin. Methods: The subjects were diabetic outpatients from April 2007 to March 2013. This resulted in the enrolment of 2246 subjects and the collection of a total of 53,968 measurements. Mean glycated haemoglobin, glycated albumin, and plasma glucose were calculated for each month over six years. The associations of the measures with each other and the average temperature for each month in Tokyo were assessed using Spearman rank correlation coefficients. Results: Plasma glucose was highest in January and lowest in May. Glycated haemoglobin was highest in March and lowest in September. Glycated albumin was highest in May and lowest in December. Glycated albumin tended to have a disjunction with plasma glucose in winter. Glycated haemoglobin had seasonal variation, but glycated albumin did not. Plasma glucose and glycated haemoglobin showed significant negative correlations with temperature (rs = −0.359, P < 0.001, rs = −0.449, P < 0.001, respectively), but glycated albumin did not. However, glycated albumin was inter-correlated with plasma glucose (rs = 0.396, P < 0.001) and glycated haemoglobin (rs = 0.685, P < 0.001), and glycated haemoglobin was inter-correlated with plasma glucose (rs = 0.465, P < 0.001). Conclusion: Glycated albumin and glycated haemoglobin showed different seasonal variations from each other over the six-year study period. Thus, further studies to identify factors that contribute to glycated albumin are needed.

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当院の症例から考えたSensor Augmented pump(SAP)の効果を最大限生かすためのポイント

大嶋洋佑, 小谷紀子, 川野義長, 税所芳史, 入江潤一郎, 田中正巳, 目黒周, 伊藤裕

糖尿病（(一社)日本糖尿病学会） 61 （ 9 ） 633 - 633 2018年09月

査読有り, ISSN 0021-437X

糖尿病性腎症第4期を有した2型糖尿病合併妊娠の1例

遠藤翔, 税所芳史, 渡辺雄佑, 菊地理恵子, 宮越敬, 川野義長, 入江潤一郎, 田中正巳, 目黒周, 伊藤裕

糖尿病（(一社)日本糖尿病学会） 61 （ 9 ） 650 - 650 2018年09月

査読有り, ISSN 0021-437X

腸内細菌・腸内環境と肥満症・糖尿病

入江潤一郎, 伊藤裕

日本内分泌学会雑誌（(一社)日本内分泌学会） 94 （ 2 ） 576 - 576 2018年09月

査読有り, ISSN 0029-0661

ステロイド治療後に血糖管理が異なる経過を示した糖尿病合併自己免疫性膵炎の2例

土屋多美, 川野義長, 西村健志, 入江潤一郎, 税所芳史, 田中正巳, 目黒周, 伊藤裕

糖尿病（(一社)日本糖尿病学会） 61 （ 9 ） 628 - 628 2018年09月

査読有り, ISSN 0021-437X

Sensor Augmented Pump(SAP)で血糖変動及びQOLが改善した1型糖尿病合併妊娠の1例

杉山和俊, 小谷紀子, 川野義長, 三石正憲, 税所芳史, 入江潤一郎, 目黒周, 田中正巳, 伊藤裕

糖尿病（(一社)日本糖尿病学会） 61 （ 9 ） 650 - 650 2018年09月

査読有り, ISSN 0021-437X

Pulmonary nocardiosis mimicking small cell lung cancer in ectopic ACTH syndrome associated with transformation of olfactory neuroblastoma: A case report

Kobayashi K., Asakura T., Ishii M., Ueda S., Irie H., Ozawa H., Saitoh K., Kurihara I., Itoh H., Betsuyaku T.

BMC Pulmonary Medicine （BMC Pulmonary Medicine） 18 （ 1 ） 2018年08月

© 2018 The Author(s). Background: Pulmonary nocardiosis frequently develops as an opportunistic infection in cell-mediated immunosuppressive patients, and sometimes requires differentiation from pulmonary malignancy. Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is a neoplastic disorder which leads to impaired cell-mediated immunity, and is commonly associated with small cell lung cancer (SCLC). Because pulmonary infection and causative malignancy can appear as pulmonary lesions with EAS, differentiation of these diseases remains a critical issue for physicians. Case presentation: A 52-year-old woman with progressive lower limb paralysis and general fatigue was referred to us. She had been diagnosed with olfactory neuroblastoma (ONB) and treated with surgery and radiation therapy 10 years before the referral and had required stereotactic radiosurgery and chemotherapy 4 years later for a relapse of the ONB. On referral, she presented with Cushing's syndrome with elevated cortisol and ACTH levels. Potassium supplement improved her symptoms; however, a month later, she was urgently hospitalized due to acute pleuritic chest pain on inspiration. Chest computed tomography revealed left lower lobular consolidations and a contralateral nodule in the right middle lobe. The clinical history and laboratory work-up suggested that her Cushing's syndrome had most likely arisen from EAS. Additionally, the lungs were suspected as the ACTH source due to high levels of progastrin-releasing peptide and progressive pulmonary consolidation with a contralateral nodule, suggesting SCLC. However, histological examination from bronchoscopy revealed no evidence of malignancy, and Nocardia cyriacigeorgica was isolated from bronchoalveolar lavage fluid. Sulfamethoxazole/trimethoprim improved her pulmonary lesions. Somatostatin receptor scintigraphy revealed strong tracer uptake in the ONB lesions, indicating that the origin of the EAS was the olfactory tumor. However, histological examination of ONB specimens resected 10 years earlier showed no intracytoplasmic immunopositivity for ACTH. Conclusions: We highlight a rare case of pulmonary nocardiosis, which was associated with EAS mimicking SCLC, and was related to ONB transformation. Nocardiosis has to be considered even though anamnestic, clinical, and radiological aspects suggest the presence of metastasis. Additionally, physicians should carefully monitor patients with ONB for the development of Cushing's symptoms because the tumor can transform into an ACTH-producing form, even after long-term follow-up.

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Expanding Phenotype of Nephronophthisis-Related Ciliopathy: An Elderly Patient with Homozygous RPGRIP1L Mutation

Kawaguchi T., Yoshida T., Hirahashi J., Uehara T., Takenouchi T., Kosaki K., Itoh H., Hayashi M.

Nephron （Nephron） 140 （ 1 ） 74 - 78 2018年08月

ISSN 16608151

© 2018 S. Karger AG, Basel. Nephronophthisis-related ciliopathies (NPHP-RC) are autosomal recessive disorders characterized by renal corticomedullary cysts with the extrarenal symptoms. Typically, patients with NPHP-RC reach end-stage kidney disease (ESKD) before the age of 30 years. We herein report a Japanese woman with NPHP-RC who had unusually delayed progression to ESKD after 6 decades. She exhibited liver dysfunction at the age of 23 years. She also showed mild renal dysfunction at the age of 43 years. Ultrasonography revealed bilateral multiple renal cysts with loss of corticomedullary differentiation. Her liver and renal functions gradually deteriorated. She was diagnosed with liver fibrosis as a result of biopsy, and initiated the maintenance hemodiafiltration therapy for ESKD at the age of 61 years. Because of a unique combination of multiple renal cysts and liver fibrosis, ciliopathy was suspected and medical exome analysis was performed. A novel homozygous missense mutation was identified in RPGRIP1L (c.1810G>A p.Glu604Lys), a causative gene for NPHP-RC. To the best of our knowledge, this patient is the oldest one who progressed to ESKD in NPHP-RC. Our case illustrates that NPHP-RC should be included in the differential diagnosis of the patient with corticomedullary polycystic kidneys accompanied by the extrarenal organ involvements, even if the patient is elderly.

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Correlation Between Lateralization Index of Adrenal Venous Sampling and Standardized Outcome in Primary Aldosteronism.

Umakoshi H, Tsuiki M, Yokomoto-Umakoshi M, Takeda Y, Takashi Y, Kurihara I, Itoh H, Katabami T, Ichijo T, Wada N, Shibayama Y, Yoshimoto T, Ashida K, Ogawa Y, Kawashima J, Sone M, Inagaki N, Takahashi K, Watanabe M, Matsuda Y, Kobayashi H, Shibata H, Kamemura K, Otsuki M, Fujii Y, Yamamto K, Ogo A, Okamura S, Miyauchi S, Fukuoka T, Izawa S, Yanase T, Hashimoto S, Yamada M, Yoshikawa Y, Kai T, Suzuki T, Kawamura T, Naruse M

Journal of the Endocrine Society 2 （ 8 ） 893 - 902 2018年08月

査読有り

Objectives: The aim of this study was to investigate the impact of adrenal venous sampling (AVS) lateralization cutoffs on surgical outcomes. Patients and Methods: Cosyntropin-stimulated AVS was used to guide surgical management of 377 patients with primary aldosteronism (PA) who were evaluated 6 months after surgery. Main Outcome Measures: The proportion of patients that achieved clinical benefit and complete biochemical success based on the AVS aldosterone lateralization index (LI) was determined. Results: Clinical benefit was achieved in 29 of 47 patients with an LI between 2 and 4, in 66 of 101 with an LI between 4 and 10, and in 158 of 203 with an LI > 10 (P < 0.01 for trend). Complete biochemical success was achieved in 27 of 42 with an LI between 2 and 4, in 60 of 76 with an LI between 4 and 10, and in 127 of 155 with an LI > 10 (P = 0.024 for trend). After adjustment for confounders and using those patients with an LI between 2 and 4 as a reference, a clinical benefit was associated only with those with an LI > 10 (OR, 2.30; 95% CI, 1.03 to 5.16), whereas complete biochemical success was associated with those with an LI between 4 and 10 (OR, 2.83; 95% CI, 1.14 to 7.01) or LI > 10 (OR, 3.55; 95% CI, 1.47 to 8.55). Conclusions: Difference of clinical outcome was relatively small when strict LI diagnostic threshold was used; biochemical cure was sufficiently achieved when an LI > 4 was used. Our study by standardized outcome measures validated that an LI > 4 may be appropriate for determining unilateral disease in PA.

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血糖コントロールの悪化が初期症状として発症した感染性心内膜炎の1例

大嶋洋佑, 田中正巳, 遠藤翔, 税所芳史, 入江潤一郎, 目黒周, 河合俊英, 伊藤裕

糖尿病（(一社)日本糖尿病学会） 61 （ 8 ） 584 - 584 2018年08月

査読有り, ISSN 0021-437X

抗精神病薬リスペリドンにて高血糖高浸透圧症候群を発症した2型糖尿病の1例

宇都飛鳥, 税所芳史, 田中正巳, 遠藤翔, 入江潤一郎, 目黒周, 河合俊英, 伊藤裕

糖尿病（(一社)日本糖尿病学会） 61 （ 8 ） 578 - 578 2018年08月

査読有り, ISSN 0021-437X

【腸内細菌と神経疾患】腸内細菌叢異常が疾病を惹起するメカニズム

入江潤一郎, 伊藤裕

神経内科（(有)科学評論社） 89 （ 2 ） 179 - 185 2018年08月

査読有り, ISSN 0386-9709

Intestinal mineralocorticoid receptor contributes to epithelial sodium channel–mediated intestinal sodium absorption and blood pressure regulation

Nakamura T., Kurihara I., Kobayashi S., Yokota K., Murai-Takeda A., Mitsuishi Y., Morisaki M., Kohata N., Oshima Y., Minami Y., Shibata H., Itoh H.

Journal of the American Heart Association （Journal of the American Heart Association） 7 （ 13 ） 2018年07月

© 2018 The Authors. Background-—Mineralocorticoid receptor (MR) has pathological roles in various cell types, including renal tubule cells, myocytes, and smooth muscle cells; however, the role of MR in intestinal epithelial cells (IECs) has not been sufficiently evaluated. The intestine is the sensing organ of ingested sodium; accordingly, intestinal MR is expected to have essential roles in blood pressure (BP) regulation. Methods and Results-—We generated IEC-specific MR knockout (IEC-MR-KO) mice. With a standard diet, fecal sodium excretion was 1.5-fold higher in IEC-MR-KO mice, with markedly decreased colonic expression of b- and c-epithelial sodium channel, than in control mice. Urinary sodium excretion in IEC-MR-KO mice decreased by 30%, maintaining sodium balance; however, a low-salt diet caused significant reductions in body weight and BP in IEC-MR-KO mice, and plasma aldosterone exhibited a compensatory increase. With a high-salt diet, intestinal sodium absorption markedly increased to similar levels in both genotypes, without an elevation in BP. Deoxycorticosterone/salt treatment elevated BP and increased intestinal sodium absorption in both genotypes. Notably, the increase in BP was significantly smaller in IEC-MR-KO mice than in control mice. The addition of the MR antagonist spironolactone to deoxycorticosterone/salt treatment eliminated the differences in BP and intestinal sodium absorption between genotypes. Conclusions-—Intestinal MR regulates intestinal sodium absorption in the colon and contributes to BP regulation. These regulatory effects are associated with variation in epithelial sodium channel expression. These findings suggest that intestinal MR is a new target for studying the molecular mechanism of hypertension and cardiovascular diseases.

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肥満と生命予後 metabolically healthy and unhealthy obesity さらなる肥満症の病態解明を!

入江潤一郎, 伊藤裕

肥満症治療学展望（日本肥満症治療学会） 6 （ 2 ） 27 - 27 2018年07月

査読有り

Adhesive intestinal obstruction increases the risk of intestinal perforation in peritoneal dialysis patients: A case report

Fujii K., Washida N., Arai E., Tsuruta M., Wakino S., Itoh H.

BMC Nephrology （BMC Nephrology） 19 （ 1 ） 2018年06月

© 2018 The Author(s). Background: Peritonitis secondary to bowel perforation is a rare and potentially fatal complication in peritoneal dialysis (PD) patients. However, the early diagnosis of bowel perforation is difficult in PD patients because the initial symptoms and signs of bowel perforation are similar to those of PD-associated peritonitis. Furthermore, the risk of bowel perforation in PD patients is unclear. Here, we present a case of intestinal perforation located at the site of adhesive intestinal obstruction in a PD patient. Case presentation: A 73-year-old man on PD presented with progressive worsening of abdominal pain and cloudy peritoneal fluid. The peritoneal fluid cell count was increased to 980/ml and peritoneal dialysis-associated peritonitis was diagnosed. Computed tomography showed local adhesions causing agglomeration of the dilated intestine. He initially responded to antibiotic treatment; however, his abdominal pain was rapidly worsened after resumption of oral intake. On hospital day 23, computed tomography showed loss of contents from the dilated intestine and discharge of fecal material from the PD tube was noted. Thus, small bowel perforation was diagnosed, and he underwent ileocecal resection with colostomy creation. As indicators of EPS was not evident, PD catheter was removed. Since then, he has been on maintenance of hemodialysis since then. Conclusion: The findings of the present case suggest that adhesive intestinal obstruction in PD patients can increase the risk of intestinal perforation. Careful monitoring for the early detection of intestinal perforation is required in such cases.

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Greater reductions in plasma aldosterone with aliskiren in hypertensive patients with higher soluble (Pro)renin receptor level article

Bokuda K., Morimoto S., Seki Y., Yatabe M., Watanabe D., Yatabe J., Ando T., Shimizu S., Itoh H., Ichihara A.

Hypertension Research （Hypertension Research） 41 （ 6 ） 435 - 443 2018年06月

ISSN 09169636

© 2018 The Japanese Society of Hypertension. The (pro)renin receptor is important in the regulation of the tissue renin-angiotensin-aldosterone system. The benefits and safety of single-aliskiren treatment without other renin-angiotensin-aldosterone system inhibitors remain unclear. The serum level of the soluble form of the (pro)renin receptor is thought to be a biomarker reflecting the activity of the tissue renin-angiotensin-aldosterone system. We investigated the effects of single renin-angiotensin-aldosterone system blockade with aliskiren on renal and vascular functions and determined if serum level of the soluble (pro)renin receptor was a predictor of aliskiren efficacy in hypertensive patients with chronic kidney disease. Thirty-nine essential hypertensive patients with chronic kidney disease in our outpatient clinic were randomly assigned to receive either aliskiren or amlodipine. The parameters associated with renal and vascular functions and indices of renin-angiotensin-aldosterone system components, including serum levels of the soluble form, were evaluated before and after 12-week and 24-week treatment. Blood pressure was not significantly different between the groups. No significant changes in serum levels were observed in the soluble (pro)renin receptor in either group. Urinary albumin, protein excretion, and cardio-ankle vascular index significantly decreased in the aliskiren group. In the aliskiren group, there was a significant negative correlation between the basal level of the soluble (pro)renin receptor and the change in plasma aldosterone concentration. Single renin-angiotensin-aldosterone system blockade with aliskiren showed renal and vascular protective effects independent of blood pressure reduction. Serum levels of the soluble (pro)renin receptor may indicate aldosterone production via the (pro)renin receptor in the adrenal gland.

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The Impact of Laparoscopic Sleeve Gastrectomy with Duodenojejunal Bypass on Intestinal Microbiota Differs from that of Laparoscopic Sleeve Gastrectomy in Japanese Patients with Obesity

Kikuchi R., Irie J., Yamada-Goto N., Kikkawa E., Seki Y., Kasama K., Itoh H.

Clinical Drug Investigation （Clinical Drug Investigation） 38 （ 6 ） 545 - 552 2018年06月

ISSN 11732563

© 2018, Springer International Publishing AG, part of Springer Nature. Background and Objectives: Bariatric surgery improves metabolic diseases and alters the intestinal microbiota in animals and humans, but different procedures reportedly have different impacts on the intestinal microbiota. We developed laparoscopic sleeve gastrectomy with duodenojejunal bypass (LSG-DJB) as an alternative to laparoscopic Roux-en-Y gastric bypass (LRYGB) in addition to laparoscopic sleeve gastrectomy (LSG) for Japanese patients with obesity. We investigated the precise change in the intestinal microbiota induced by these procedures in the present study. Methods: A prospective observational study of 44 Japanese patients with obesity was conducted [22 patients underwent LSG, 18 underwent LSG-DJB, and 4 underwent laparoscopic adjustable gastric banding (LAGB)]. The patients’ clinical parameters and intestinal microbiota were investigated before and for 6 months after surgery. The microbiota was analyzed by a 16S rDNA method. Results: LSG and LSG-DJB significantly improved the metabolic disorders in the patients with obesity. The proportion of the phylum Bacteroidetes and order Lactobacillales increased significantly in the LSG group, and that of the order Enterobacteriales increased significantly in the LSG-DJB group. Conclusions: LSG and LSG-DJB improved obesity and type 2 diabetes in Japanese patients with obesity, but the impact of LSG-DJB on the intestinal microbiota differed from that of LSG. This difference in the impact on the intestinal environment could explain the different efficacies of LSG and LSG-DJB in terms of their ability to resolve metabolic disorders in the clinical setting.

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Intensive treat-to-target statin therapy in high-risk Japanese patients with hypercholesterolemia and diabetic retinopathy: Report of a randomized study

Itoh H., Komuro I., Takeuchi M., Akasaka T., Daida H., Egashira Y., Fujita H., Higaki J., Hirata K., Ishibashi S., Isshiki T., Ito S., Kashiwagi A., Kato S., Kitagawa K., Kitakaze M., Kitazono T., Kurabayashi M., Miyauchi K., Murakami T., Murohara T., Node K., Ogawa S., Saito Y., Seino Y., Shigeeda T., Shindo S., Sugawara M., Sugiyama S., Terauchi Y., Tsutsui H., Ueshima K., Utsunomiya K., Yamagishi M., Yamazaki T., Yo S., Yokote K., Yoshida K., Yoshimura M., Yoshimura N., Nakao K., Nagai R.

Diabetes Care （Diabetes Care） 41 （ 6 ） 1275 - 1284 2018年06月

ISSN 01495992

© 2018 by the American Diabetes Association. OBJECTIVE Diabetes is associated with high risk of cardiovascular (CV) events, particularly in patients with dyslipidemia and diabetic complications. We investigated the incidence of CV events with intensive or standard lipid-lowering therapy in patients with hypercholesterolemia, diabetic retinopathy, and no history of coronary artery disease (treat-to-target approach). RESEARCH DESIGN AND METHODS In this multicenter, prospective, randomized, open-label, blinded end point study, eligible patients were randomly assigned (1:1) to intensive statin therapy targeting LDL cholesterol (LDL-C) <70 mg/dL (n = 2,518) or standard statin therapy targeting LDL-C 100-120 mg/dL (n = 2,524). RESULTS Mean follow-up was 37± 13months. LDL-C at 36 months was 76.5± 21.6mg/dL in the intensive group and 104.1 ± 22.1 mg/dL in the standard group (P < 0.001). The primary end point events occurred in 129 intensive group patients and 153 standard group patients (hazard ratio [HR] 0.84 [95% CI 0.67-1.07]; P = 0.15). The relationship between the LDL-C difference in the two groups and the event reduction rate was consistent with primary prevention studies in patients with diabetes. Exploratory findings showed significantly fewer cerebral events in the intensive group (HR 0.52 [95% CI 0.31-0.88]; P = 0.01). Safety did not differ significantly between the two groups. CONCLUSIONS We found no significant decrease in CV events or CV-associated deaths with intensive therapy, possibly because our between-group difference of LDL-C was lower than expected (27.7 mg/dL at 36 months of treatment). The potential benefit of achieving LDL-C <70 mg/dL in a treat-to-target strategy in high-risk patients deserves further investigation.

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Nanogel-based nasal vaccines for infectious and lifestyle-related diseases

Azegami T., Yuki Y., Nakahashi R., Itoh H., Kiyono H.

Molecular Immunology （Molecular Immunology） 98 19 - 24 2018年06月

ISSN 01615890

© 2017 Because the mucosa is the major entry route for most pathogens, the development of mucosal vaccines is a rational approach for protecting against these undesired agents. Mucosal administration of vaccine antigen is useful for non-infectious chronic diseases as well, because of its advantages over injection routes, including comparable efficacy in the induction of systemic immune responses, less pain, and no risk of adverse events at the injection site. However, because it is difficult to effectively induce and regulate antigen-specific mucosal and systemic immune responses when antigen alone is mucosally administered, an appropriate form of mucosal delivery vehicle must be used. Antigen delivery systems involving nanogels, which act as artificial chaperones and mucosal adhesives, are a promising approach to overcoming this problem. Here, we introduce current perspectives regarding the development of nanogel-based nasal vaccines for both infectious and lifestyle-related diseases.

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