Papers - KITAMURA Kazuo
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両側腎動脈狭窄症に対する治療 Reviewed
菊池正雄、古郷博紀、石﨑友梨、菅井亜希、新屋琴子、麻生久美子、皆川明大、西園隆三、稲垣浩子、石川哲憲、佐藤祐二、北村和雄、藤元昭一
宮崎県医師会医学会誌 44 ( 1 ) 68 - 72 2020.3
Language：Japanese Publishing type：Research paper (scientific journal)
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Developments of human adrenomedullin-IgG1 Fc fusion proteins Reviewed
Nagata S., Yamasaki M., Kawano A., Kitamura K.
Journal of Biochemistry 25 ( 1 ) 157 - 162 2020.1
Publishing type：Research paper (scientific journal) Publisher：Journal of Biochemistry
Human adrenomedullin (hAM) is a hypotensive peptide hormone that exerts powerful anti-inflammatory effects. However, treatment required continuous administration of hAM, as the half-life of native hAM is quite short in blood. To resolve this problem, we designed two kinds of human IgG1 Fc fusion proteins containing either full-length hAM (IgG1-AM) or hAM residues 6-52 [IgG1-AM (6-52)]. A DNA construct was constructed by connecting DNA sequences encoding hAM and the IgG1 Fc region with a DNA sequence encoding a (GGGGS)<inf>3</inf> linker. The molecular weights of IgG1-AM and IgG1-AM (6-52) were determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and gel filtration chromatography. By protein sequencing, the N-terminal sequence of both recombinant AM-Fc fusions showed the expected human IgG1 sequence. Sufficient concentrations of both AM-Fc fusions were observed in blood 2 days after a single subcutaneous administration. IgG1-AM and IgG1-AM (6-52) stimulated cAMP production in human embryonic kidney-293 cells stably expressing the AM1 receptor. The activity of IgG1-AM (6-52) was higher than that of IgG1-AM. Treatment with IgG1-AM (6-52) inhibited blood pressure increase in spontaneously hypertensive rats. In addition, IgG1-AM (6-52) reduced total inflammation scores in the dextran sulfate sodium colitis model. Therefore, AM-IgG1 Fc fusions represent potential novel therapeutic agents.
DOI： 10.1093/jb/mvz023
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中高齢発症のクローン病患者の臨床像 Reviewed
野田貴穂、山本章二朗、河上洋、三池忠、貴島翔子、米澤瑛美、市成直樹、坂元一樹、中村佳菜子、鈴木翔、夏田朱一郎、橋本神奈、山路卓巳、安倍弘生、芦塚伸也、田原良博、下田和哉、稲津東彦、北村和雄
日本消化器病学会雑誌 117 ( suppl-1 ) A279 - A279 2020
Publishing type：Research paper (scientific journal)
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アドレノメデュリン Reviewed
北村和雄
日本臨牀 78 ( 1 ) 335 - 342 2020
Publishing type：Research paper (scientific journal)
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Association between body mass index (BMI) variability and plasma adrenomedullin (AM) in the general population Reviewed
加藤丈司、川越由紀子、姜丹鳳、北村和雄
Folia Endocrinologica Japonica 96 ( 4 ) 1123 - 1123 2020
Publishing type：Research paper (scientific journal)
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ヒトIgGのFc領域を融合したアドレノメデュリン誘導体の開発 Reviewed
永田さやか、山﨑基生、北村和雄
日本内分泌学会雑誌 96 ( 1 ) 298 - 298 2020
Publishing type：Research paper (scientific journal)
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アドレノメデュリンによるIBD治療 Reviewed
芦塚伸也、稲津東彦、北俊弘、北村和雄
IBD Research 14 ( 3 ) 183 - 191 2020
Publishing type：Research paper (scientific journal)
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Minakawa A., Fukuda A., Sato Y., Kikuchi M., Kitamura K., Wiggins R.C., Fujimoto S.
Scientific Reports 9 ( 1 ) 18485 2019.12
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Scientific Reports
Type2 diabetes-associated nephropathy is the commonest cause of renal failure. Mechanisms responsible are controversial. Leptin-deficient hyperphagic Zucker (fa/fa) rats were modeled to test the hypothesis that glomerular enlargement drives podocyte hypertrophic stress leading to accelerated podocyte detachment, podocyte depletion, albuminuria and progression. By 6weeks, prior to development of either hyperglycemia or albuminuria, fa/fa rats were hyperinsulinemic with high urinary IGF1/2 excretion, gaining weight rapidly, and had 1.6-fold greater glomerular volume than controls (P < 0.01). At this time the podocyte number per glomerulus was not yet reduced although podocytes were already hypertrophically stressed as shown by high podocyte phosphor-ribosomal S6 (a marker of mTORC1 activation), high urinary pellet podocin:nephrin mRNA ratio and accelerated podocyte detachment (high urinary pellet podocin:aquaporin2 mRNA ratio). Subsequently, fa/fa rats became both hyperglycemic and albuminuric. 24 hr urine albumin excretion correlated highly with decreasing podocyte density (R2 = 0.86), as a consequence of both increasing glomerular volume (R2 = 0.70) and decreasing podocyte number (R2 = 0.63). Glomerular podocyte loss rate was quantitatively related to podocyte detachment rate measured by urine pellet mRNAs. Glomerulosclerosis occurred when podocyte density reached <50/106um3. Reducing food intake by 40% to slow growth reduced podocyte hypertrophic stress and “froze” all elements of the progression process in place, but had small effect on hyperglycemia. Glomerular enlargement caused by high growth factor milieu starting in pre-diabetic kidneys appears to be a primary driver of albuminuria in fa/fa rats and thereby an under-recognized target for progression prevention. Progression risk could be identified prior to onset of hyperglycemia or albuminuria, and monitored non-invasively by urinary pellet podocyte mRNA markers.
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Polyethylene glycol-conjugated human adrenomedullin as a possible treatment for vascular dementia Reviewed
Nagata S., Yamasaki M., Kitamura K.
Peptides 121 170133 2019.11
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Peptides
Adrenomedullin (AM) is a multifunctional bioactive peptide. Recent studies have shown that AM has protective effects against ischemic brain damage. We recently prepared a long-acting human AM derivative that was conjugated with a 60 kDa polyethylene glycol (PEG-AM), which had an effect similar to that of native AM. In this study, we examined the effect of PEG-AM on four-vessel occlusion model rats, which exhibit vascular dementia. From day 10 to day 14 after surgery, the learning and memory abilities of the rats were examined using a Morris water maze. The rats were treated with a single subcutaneous injection of 1.0 or 10.0 nmol/kg of PEG-AM. PEG-AM treatment reduced the escape latency in the hidden platform test. Furthermore, the treatment increased the time spent in the platform quadrant in the probe test. The data showed that PEG-AM injection prevented memory loss and learning disorders in dose-dependent manner. On day 14, the immunoreactive AM concentration in plasma was 9.749 ± 2.167 pM in the high-dose group (10.0 nmol/kg) and 0.334 ± 0.073 pM in the low-dose group (1.0 nmol/kg). However, even in the low-dose group, a significant effect was observed in both tests. The present data indicate that PEG-AM is a possible therapeutic agent for the treatment of ischemic brain injury or vascular dementia.
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Tsuruda T., Funamoto T., Udagawa N., Kurogi S., Nakamichi Y., Koide M., Chosa E., Asada Y., Kitamura K.
European Journal of Pharmacology 859 172519 2019.9
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：European Journal of Pharmacology
Juvenile Paget disease (JPD1), an autosomal-recessive disorder, is characterized by extremely rapid bone turnover due to osteoprotegerin deficiency. Its extra-skeletal manifestations, such as hypertension and heart failure, suggest a pathogenesis with shared skeletal and cardiovascular system components. In spite of this, the effects of anti-hypertensive drugs on bone morphometry remain unknown. We administered an angiotensin II type 1 receptor blocker, olmesartan (5 mg/kg/day) to 8-week-old male mice lacking the osteoprotegerin gene, with and without 1 μg/kg/min of angiotensin II infusion for 14 days. Olmesartan treatment decreased systolic blood pressure, and echocardiography showed increased left ventricular systolic contractility. Three-dimensional micro-computed tomography scans demonstrated that olmesartan treatment increased trabecular bone volume (sham, +176%; angiotensin II infusion, +335%), mineral density (sham, +150%; angiotensin II infusion, +313%), and trabecular number (sham, +407%; angiotensin II infusion, +622%) in the tibia. Olmesartan increased cortical mineral density (sham, +19%; angiotensin II infusion, +24%), decreased the cortical bone section area (sham, −16%; angiotensin II infusion, −18%), decreased thickness (sham, −18%; angiotensin II infusion, −31%), and decreased the lacunar area (sham, −41%; angiotensin II infusion, −27%) in the tibia. Similar trend was observed in the femur. Moreover, olmesartan decreased angiotensin II-induced increases in tartrate-resistant acid phosphatase concentrations in plasma, but it affected neither type I procollagen N-terminal propeptides, nor the receptor activator of nuclear factor kappa-B ligand. Our data suggest that blockade of the angiotensin II type 1 receptor improves bone vulnerability, and helps to maintain the heart's structural integrity in osteoprotegerin-deficient mice.
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Tsuruda T., Sato Y., Kajihara K., Kawabata T., Kubuki Y., Komaki S., Kikuchi M., Ishikawa T., Tono T., Kitamura K.
Frontiers in Cardiovascular Medicine 6 2019.8
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Frontiers in Cardiovascular Medicine
We describe the case of a patient with neuroendocrine ethmoid sinus carcinoma, who exhibited markedly elevated levels of serum cardiac troponin-T and creatine kinase (CK)-MB isoenzyme without any symptom after the administration of nivolumab, immune checkpoint inhibitor. The repeated 12-leads-electrocardiogram did not show any changes in the ST-T segments or arrhythmias. The echocardiogram showed normal ranges of left ventricular contraction in the clinical course. Cardiac magnetic resonance imaging showed minimal myocardial edema and inflammation. Blood clots in the metastatic lesion of bone marrow aspirates exhibited positive staining for cardiac troponin-T and CK-MB in the cytoplasm and nucleoplasm of neoplastic cells. Although we did not perform a second cardiac magnetic resonance imaging and autopsy, we postulate that the attack of the neoplastic cells by the immune checkpoint inhibitor or the secretion from neoplastic cell-derived extracellular vesicles may have exacerbated the increase in concentrations of these molecules in the blood. Our case should warrant consideration a false-positive value of cardiac troponin-T and CK-MB can be obtained in cases with malignancy.
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血圧変動性と動脈硬化度および動脈リモデリング Reviewed
北 俊弘、北村和雄
血圧 26 ( 4 ) 202 - 203 2019.8
Language：Japanese Publishing type：Research paper (scientific journal)
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コントロールの難しい高血圧患者の修正可能な因子 Reviewed
北 俊弘、北村和雄
血圧 26 ( 8 ) 442 - 443 2019.8
Language：Japanese Publishing type：Research paper (scientific journal)
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Efficient screening of patients with aldosterone-producing adenoma using the ACTH stimulation test Reviewed
Kita T., Furukoji E., Sakae T., Kitamura K.
Hypertension Research 42 ( 6 ) 801 - 806 2019.6
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Hypertension Research
Adrenal venous sampling (AVS) is the gold standard test for distinguishing between unilateral and bilateral primary aldosteronism (PA); however, AVS requires advanced and time consuming technique. The needs for AVS have been increasing due to the increased utilization of screening for PA. An efficient selection of unilateral PA, such as aldosterone-producing adenoma (APA), before AVS is useful to avoid undesirable AVS in bilateral PA, such as idiopathic hyperaldosteronism. In this study, 40 patients who received all three confirmatory tests, including the captopril challenge test, furosemide upright test and adrenocorticotropin (ACTH) stimulation test (AST), and who were diagnosed as having PA by AVS were recruited. Subjects were diagnosed as having unilateral aldosterone excess (n = 22) or bilateral aldosterone excess (n = 18) by AVS. All patients with unilateral PA underwent an operation and were finally diagnosed with APA. Major differences were detected in serum potassium level, basal plasma aldosterone concentration (PAC), presence of adrenal tumor, and AST results between the two groups. The PAC/cortisol ratio at 120 min in the AST showed the highest diagnostic capability for distinguishing the subtypes of PA according to a receiver operating characteristic (ROC) curve analysis (area under the ROC curve was 0.956). At a cutoff value of 1.20 for the PAC/cortisol ratio at 120 min on the AST, the sensitivity was 95.5%, and the specificity was 88.9%. This sufficiently high sensitivity suggests that the PAC/cortisol ratio at 120 min in the AST could be useful for the screening of patients with PA who are suitable for AVS.
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【高血圧診療の新展開】降圧薬選択の基本と併用療法 Reviewed
北 俊弘、北村和雄
循環器内科 85 ( 6 ) 773 - 778 2019.6
Language：Japanese Publishing type：Research paper (scientific journal)
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Toida T., Sato Y., Komatsu H., Kitamura K., Fujimoto S.
Blood Purification 47 ( Suppl2 ) 50 - 55 2019.4
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Blood Purification
Background/Aims: Uric acid (UA) levels are affected by changes in dialysis; however, the relationship between the pre-and postdialysis UA difference (UAD) and mortality remains unclear. Methods: A total of 1,073 patients receiving maintenance hemodialysis (HD) were enrolled in this cohort study and followed up for 5 years. Patients were divided into quartile categories according to baseline UAD. Coxs regression analyses were used to investigate the relationship between UAD categories and all-cause and cardiovascular (CV) mortalities while adjusting for potential confounders. Results: A total of 280 patients died of all causes, including 121 CV deaths, during the follow-up. In the analysis for all-cause mortality, hazard ratios were significantly higher in the lowest UAD group (< 4.7 mg/dL) than in the highest UAD group (> 6.2 mg/dL). A correlation was not observed with CV mortality. Conclusion: UAD correlated with all-cause mortality. UAD may be the most appropriate reference for controlling UA in HD patients.
DOI： 10.1159/000496638
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尿中ビッグアンジオテンシン-25の測定系の確立と測定意義の解明 Reviewed
永田さやか、北村和雄
日本内分泌学会雑誌 95 ( 1 ) 377 - 377 2019.4
Language：Japanese Publishing type：Research paper (scientific journal)
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Toida T., Toida R., Yamashita R., Komiya N., Uezono S., Komatsu H., Ishikawa T., Kitamura K., Sato Y., Fujimoto S.
CardioRenal Medicine 9 ( 3 ) 190 - 200 2019.3
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：CardioRenal Medicine
Background: Left ventricular diastolic dysfunction (LVDD) causes heart failure with a preserved left ventricular ejection fraction (LVEF) in the general population. Objective: To examine the relationships between the LVDD grades of the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging (ASE/EACVI) recommendations and several arteriosclerotic parameters and major cardiovascular events (MACE) in hemodialysis patients with preserved LVEF. Method: Sixty-three prevalent hemodialysis patients (median age [interquartile range], 69 [64-75] years, 31.7% female) with normal systolic function (LVEF > 50%) were enrolled. LVDD evaluated by echocardiography at baseline was divided into three groups according to ASE/EACVI recommendations (normal diastolic function [ND], n = 24; intermediate, n = 19; diastolic dysfunction [DD], n = 20). All patients underwent analyses of several arteriosclerotic parameters (carotid intima-media thickness [CIMT], plaque score [PS], ankle brachial index [ABI], and brachial-ankle pulse wave velocity [baPWV]). The presence or absence of postdialysis orthostatic hypotension was assessed in each dialysis session. MACE during the 1-year follow-up period was obtained from medical records. Kaplan-Meier and Cox's regression analyses were used to investigate the relationship between LVDD grades and MACE. Results: Postdialysis orthostatic hypotension and PS, but not CIMT, ABI, or baPWV, increased proportionally with LVDD grades. Eleven patients developed MACE, including 2 cardiovascular deaths. The Kaplan-Meier analysis showed that MACE frequently occurred in the DD grade (p = 0.002 by the log-rank test). Cox's regression analysis adjusted for potential confounders (age, sex, diabetes, systolic blood pressure, and body mass index) revealed that the DD grade was associated with MACE when the ND grade was set as a reference. Conclusions: In maintenance hemodialysis patients with normal ventricular systolic function, a classification of LVDD by the 2016 ASE/EACVI recommendations may be a useful tool for predicting cardiovascular events.
DOI： 10.1159/000496064
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Onitsuka H., Koyama S., Ideguchi T., Ishikawa T., Kitamura K., Nagamachi S.
Medicine (United States) 98 ( 8 ) 2019.2
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Medicine (United States)
Recent studies reported that high doses of short-acting loop diuretics are associated with poor outcomes in patients with heart failure (HF). Short-acting loop diuretics have been shown to activate the renin-angiotensin system (RAS) and have no favorable effects on cardiac sympathetic nervous system (SNS) activity. The goal of this study is to investigate the relationship between daily doses of furosemide and the outcomes of patients with left ventricular dysfunction (LVD) from the viewpoint of cardiac SNS abnormalities using iodine-123-labeled metaiodobenzylguanidine (123l-MIBG) myocardial scintigraphy. We enrolled 137 hospitalized patients (62.5±14.2 years old, 103 men) with LVEF < 45% who underwent 123l-MIBG myocardial scintigraphy. A delayed heart-to-mediastinum ratio (delayed HMR) was assessed using 123l-MIBG scintigraphy. Cardiac events were defined as cardiac death or re-hospitalization due to the deterioration of HF. Cox proportional hazard analysis was used to identify predictors of cardiac events. Cardiac events occurred in 57 patients in a follow-up period of 33.1±30 months. In a multivariate Cox proportional hazard analysis, delayed HMR and furosemide doses were identified as independent predictors of cardiac events (P=.0042, P=.033, respectively). Inverse probability of treatment weighting Cox modeling showed that the use of furosemide (≥40mg /day) was associated with cardiac events with a hazard ratio of 1.96 (P=.003). In the Kaplan-Mayer analysis, the cardiac event-free survival rate was significantly lower in patients treated with high doses of furosemide (≥60mg/day vs 40-60mg/day vs <40mg/day, the Log-rank test P<.0001). In a receiver-operating characteristic (ROC) analysis, the cut-off value for cardiac events was 40mg/day of furosemide. The cardiac event-free rate was significantly lower in patients with delayed HMR <1.8 (median value) and receiving furosemide ≥40mg/day than in other patients (the Log-rank test P<.0001). Significant differences in cardiac event rates according to furosemide doses among patients with delayed HMR <1.8 were observed among patients without b-blocker therapy (P=.001), but not among those with b-blocker therapy (P=.127). The present results indicate that a relationship exists between higher doses of furosemide and poor outcomes. The prognosis of HF patients with severe cardiac SNS abnormalities receiving high-dose short-acting loop diuretics is poor.
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Kinoshita Y., Arita S., Murazoe H., Kitamura K., Ashizuka S., Inagaki-Ohara K.
Human Cell 32 ( 1 ) 12 - 21 2019.1
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Human Cell
Adrenomedullin (AM) exerts a potent anti-inflammatory effect. Intrarectal or consecutive intravenous administrations of AM reduce pathological manifestations in rodent colitis models. However, in clinical applications, a safer administration route that provides stronger alleviation of patient burden is preferred. We investigated whether subcutaneously administered AM is effective against dextran sulfate sodium (DSS)-induced colitis. C57BL/6J mice were administered 1% DSS in drinking water and received AM at 8, 40 or 80 nmol/kg subcutaneously once a day for 7 consecutive days. Subcutaneously administered AM significantly and dose-dependently ameliorated body weight loss, diarrhea, and histological severity of colonic inflammation in DSS-treated mice. The AM therapeutic effect was associated with the upregulation of the production of autocrine AM, and expression of cAMP, c-fos, KLF4, and downregulation of STAT3 and NF-κB p65 phosphorylation, as well as a decrease in proinflammatory cytokine expression in the colon. Subcutaneous AM treatment potently attenuated DSS-induced colitis, which suggests that AM administered subcutaneously in ulcerative colitis (UC) patients may decrease diseases burden and improve quality of life.