Papers - KITAMURA Kazuo
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CALMODULIN BINDING PEPTIDES IDENTIFIED IN PORCINE BRAIN Reviewed
Kazuo Kitamura, Kenji Kangawa and Hisayuki Matsuo
Protein Research Foundation, 1986
Authorship：Lead author Publishing type：Research paper (scientific journal)
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Cloning and characterization of cDNA encoding a precursor for human adrenomedullin Reviewed
K Kitamura 1, J Sakata, K Kangawa, M Kojima, H Matsuo, T Eto
Biochem Biophys Res Commun . 30 ( 194（2） ) 720 - 725 1993.7
Publishing type：Research paper (scientific journal)
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Adrenomedullin a novel hypotensive peptide isolated from human pheochromocytoma Reviewed
K Kitamura 1, K Kangawa, M Kawamoto, Y Ichiki, S Nakamura, H Matsuo, T Eto
Biochem Biophys Res Commun . 30 ( 192（2） ) 553 - 560 1993.4
Publishing type：Research paper (scientific journal)
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Purification and characterization of rat skeletal muscle fructose-6-phosphate,2-kinase fructose-2,6-bisphatase Reviewed
K Kitamura 1, K Uyeda, K Kangawa, H Matsuo
J Biol Chem 15 ( 264（17） ) 9799 - 9806 1989.6
Publishing type：Research paper (scientific journal)
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Purification and characterization of myocardial fructose-6-phosphate,2-kinase and fructose-2,6-bisphosphatase Reviewed
K Kitamura , K Uyeda
J Biol Chem 1988.6
Publishing type：Research paper (scientific journal)
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Adrenomedullin - Physiological regulator of the cardiovascular system or biochemical curiosity? Reviewed
Kitamura K., Eto T.
Current Opinion in Nephrology and Hypertension 6 ( 1 ) 80 - 87 1997.3
Authorship：Lead author Publishing type：Research paper (scientific journal) Publisher：Current Opinion in Nephrology and Hypertension
Adrenomedullin is a potent vasodilator peptide that exerts major effects on cardiovascular function. Adrenomedullin is biosynthesized in a wide variety of organs and cells, although it was initially isolated from human pheochromocytoma tissue. In addition to adrenomedullin, proadrenomedullin N-terminal 20 peptide was found to be processed from adrenomedullin precursor. Both adrenomedullin and proadrenomedullin N-terminal 20 peptide show hypotensive effects in anesthetized rats, but exhibit different hypotensive mechanisms. Further, adrenomedullin possesses multiple biological effects involved in cardiovascular homeostasis. Plasma adrenomedullin concentration is increased in patients with cardiovascular diseases such as hypertension, congestive heart failure, renal failure and septic shock. The present review summarizes the recent advancement of adrenomedullin research and demonstrates that adrenomedullin is one of the important vasoactive peptides involved in the physiology and pathophysiology of circulatory control and control of body fluid.
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Adrenomedullin Therapy for Moderate-to-Severe COVID-19 Pneumonia: Double-Blind Placebo-Controlled Phase 2a Trial. Reviewed
Kita T, Ohmagari N, Saito S, Mukae H, Takazono T, Nakada TA, Shimada T, Hirai Y, Shindo Y, Komiya K, Saito A, Yamato M, Homma K, Okamoto M, Yamamoto Y, Mutoh Y, Hasegawa C, Mori N, Nakamura-Uchiyama F, Honda M, Tomii K, Ishii H, Takajo I, Watanabe K, Kitamura K
Viruses 17 ( 7 ) 2025.7
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Mochizuki T., Manita S., Shimura H., Kira S., Sawada N., Bito H., Sakimura K., Augustine G.J., Mitsui T., Takeda M., Kitamura K.
Scientific Reports 14 ( 1 ) 2024.12
Publishing type：Research paper (scientific journal) Publisher：Scientific Reports
Lower urinary tract (LUT) function is controlled by the central nervous system, including higher-order cognitive brain regions. The anterior cingulate cortex (ACC) is one of these regions, but the role of its activity in LUT function remains poorly understood. In the present study, we conducted optogenetic experiments to manipulate neural activity in mouse ACC while monitoring bladder pressure to elucidate how the activity of ACC regulates LUT function. Selective optogenetic stimulation of excitatory neurons in ACC induced a sharp increase in bladder pressure, whereas activation of inhibitory neurons in ACC prolonged the interval between bladder contractions. Pharmacological manipulation of ACC also altered bladder contractions, consistent with those observed in optogenetic experiments. Optogenetic mapping of the cortical area responsible for eliciting the increase in bladder pressure revealed that stimulation to ACC showed more potent effects than the neighboring motor cortical areas. These results suggest that ACC plays a crucial role in initiating the bladder pressure change and the micturition reflex. Thus, the balance between excitation and inhibition in ACC may regulate the reflex bidirectionally.
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Yoshimoto T., Saito S., Omae K., Tanaka K., Kita T., Kitamura K., Fukuma K., Washida K., Abe S., Ishiyama H., Yamaguchi E., Yamagami H., Nagatsuka K., Tsuji M., Minami M., Yamamoto H., Hattori Y., Tanaka T., Ihara M.
eClinicalMedicine 77 2024.11
Publishing type：Research paper (scientific journal) Publisher：eClinicalMedicine
Background: Adrenomedullin has angiogenic and vasoprotective effects in acute ischemic stroke (AIS). This investigator-initiated trial aimed to evaluate the safety, efficacy, and optimal administration of adrenomedullin in treating AIS. Methods: In this single-center, multi-cohort, double-blinded, randomized, placebo-controlled, Phase II trial, patients with AIS received pulsed adrenomedullin (9 ng/kg/min for 8 h daily over 7 days) or placebo in the first-half cohort, and continuous-pulsed adrenomedullin (9 ng/kg/min for 72 h during the first 3 days and 8 h daily between Day 4–7) or placebo in the second-half cohort. We included male and female patients aged 20–90 years with newly confirmed ischemic lesions on diffusion-weighted magnetic resonance imaging, and for whom protocol treatment could be initiated within 24 h of symptom onset. The primary safety endpoint was the occurrence of intervention-related severe adverse events. For the primary efficacy endpoint, the least square means and 95% confidence intervals of National Institutes of Health Stroke Scale (NIHSS) scores up to 7 days post-intervention initiation were calculated using generalized estimating equation models. This trial was registered at Japan Registry of Clinical Trials, jRCT2051190092. Findings: Between January 16, 2020, and November 14, 2021, 60 patients were enrolled (median [interquartile range] age, 75 [66–81] years; NIHSS score, 3 [2–4]; 21 [35.0%] females). Neither intervention-related serious adverse events nor severe adverse events were observed in patients receiving adrenomedullin. No life-threatening adverse events or deaths were reported. The least square means (95% confidence intervals) of the changes in NIHSS scores from pre-treatment to Day 7 were −0.76 (−1.43 to −0.09) in the adrenomedullin group (−1.08 [−2.17 to 0.00] in the pulsed adrenomedullin group and −0.42 [−1.12 to 0.29] in the continuous-pulsed adrenomedullin group) and −1.08 (−2.11 to −0.05) in the placebo group. Interpretation: Adrenomedullin was well tolerated in patients with non-severe, non-embolic AIS, although its beneficial effects were not demonstrated. It is necessary to show the efficacy of adrenomedullin in further clinical trials. Funding: Japan Agency for Medical Research and Development.
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Efficacy and safety of adrenomedullin for acute ischemic stroke (AMFIS): a phase 2, randomized, double-blinded, placebo-controlled, clinical trial Reviewed
Takeshi YoshimotoTakeshi Yoshimoto , Satoshi Saito , Katsuhiro Omae , Kenta Tanaka, Toshihiro Kita , Kazuo Kitamura Masafumi Ihara
EClinicalMedicine 13 ( 77 ) 102901 2024.10
Publishing type：Research paper (scientific journal)
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A multicolor suite for deciphering population coding of calcium and cAMP in vivo Reviewed
Yokoyama T., Manita S., Uwamori H., Tajiri M., Imayoshi I., Yagishita S., Murayama M., Kitamura K., Sakamoto M.
Nature Methods 21 ( 5 ) 897 - 907 2024.5
Publishing type：Research paper (scientific journal) Publisher：Nature Methods
cAMP is a universal second messenger regulated by various upstream pathways including Ca2+ and G-protein-coupled receptors (GPCRs). To decipher in vivo cAMP dynamics, we rationally designed cAMPinG1, a sensitive genetically encoded green cAMP indicator that outperformed its predecessors in both dynamic range and cAMP affinity. Two-photon cAMPinG1 imaging detected cAMP transients in the somata and dendritic spines of neurons in the mouse visual cortex on the order of tens of seconds. In addition, multicolor imaging with a sensitive red Ca2+ indicator RCaMP3 allowed simultaneous measurement of population patterns in Ca2+ and cAMP in hundreds of neurons. We found Ca2+-related cAMP responses that represented specific information, such as direction selectivity in vision and locomotion, as well as GPCR-related cAMP responses. Overall, our multicolor suite will facilitate analysis of the interaction between the Ca2+, GPCR and cAMP signaling at single-cell resolution both in vitro and in vivo.
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Washida K., Saito S., Tanaka T., Nakaoku Y., Ishiyama H., Abe S., Kuroda T., Nakazawa S., Kakuta C., Omae K., Tanaka K., Minami M., Morita Y., Fukuda T., Shindo A., Maki T., Kitamura K., Tomimoto H., Aso T., Ihara M.
Cerebral Circulation - Cognition and Behavior 6 2024.1
Publishing type：Research paper (scientific journal) Publisher：Cerebral Circulation - Cognition and Behavior
Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common form of hereditary cerebral small vessel disease (SVD), currently lacks disease-modifying treatments. Adrenomedullin (AM), a vasoactive peptide with angiogenic, vasodilatory, anti-inflammatory, and anti-oxidative properties, shows potential effects on the neuro-glial-vascular unit. Objective: The AdrenoMedullin for CADASIL (AMCAD) study aims to assess the efficacy and safety of AM in patients with CADASIL. Sample size: Overall, 60 patients will be recruited. Methods: The AMCAD is a multicenter, investigator-initiated, single-arm phase II trial. Patients with a confirmed CADASIL diagnosis, based on NOTCH3 genetic testing, will receive an 8-h AM treatment (15 ng/kg/min) for 14 days following a baseline assessment (from day 1 to day 14). Follow-up evaluations will be performed on days 15, 28, 90, and 180. Study outcomes: The primary endpoint is the cerebral blood flow change rate in the frontal cortex, evaluated using arterial spin labeling magnetic resonance imaging, from baseline to day 28. Summary statistics, 95% confidence intervals, and a one-sample t-test will be used for analysis. Conclusion: The AMCAD study aims to represent the therapeutic potential of AM in patients with CADASIL, addressing an unmet medical need in this challenging condition. Clinical Trial Registration: jRCT 2,051,210,117 (https://jrct.niph.go.jp/en-latest-detail/jRCT2051210117).
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Acyl modifications in bovine, porcine, and equine ghrelins Reviewed
Ida T., Tominaga H., Iwamoto E., Kurogi A., Okura A., Shimada K., Kato J., Kuwano A., Ode H., Nagata S., Kitamura K., Yazawa T., Sato-Hashimoto M., Yasuda M., Miyazato M., Shiimura Y., Sato T., Kojima M.
Frontiers in Endocrinology 15 2024
Publishing type：Research paper (scientific journal) Publisher：Frontiers in Endocrinology
Ghrelin is a peptide hormone with various important physiological functions. The unique feature of ghrelin is its serine 3 acyl-modification, which is essential for ghrelin activity. The major form of ghrelin is modified with n-octanoic acid (C8:0) by ghrelin O-acyltransferase. Various acyl modifications have been reported in different species. However, the underlying mechanism by which ghrelin is modified with various fatty acids remains to be elucidated. Herein, we report the purification of bovine, porcine, and equine ghrelins. The major active form of bovine ghrelin was a 27-amino acid peptide with an n-octanoyl (C8:0) modification at Ser3. The major active form of porcine and equine ghrelin was a 28-amino acid peptide. However, porcine ghrelin was modified with n-octanol (C8:0), whereas equine ghrelin was modified with n-butanol (C4:0) at Ser3. This study indicates the existence of structural divergence in ghrelin and suggests that it is necessary to measure the minor and major forms of ghrelin to fully understand its physiology.
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A Case of New Electrocardiographic Changes During a Routine Health Checkup Requiring Urgent Cardiologist Consultation Reviewed
KAWANO Sayaka, KITAMURA Kazuo
Health Evaluation and Promotion 51 ( 4 ) 409 - 411 2024
Publishing type：Research paper (scientific journal)
DOI： 10.7143/jhep.2024-26
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Kawaguchi M., Kataoka H., Kiwaki T., Weiting L., Nagata S., Kitamura K., Fukushima T.
FEBS Open Bio 13 ( 4 ) 713 - 723 2023.4
Publishing type：Research paper (scientific journal) Publisher：FEBS Open Bio
Adrenomedullin (AM) is a peptide with pleiotropic physiological functions that attenuates intestinal mucosal inflammation. However, the mechanism underpinning mucosal protection by AM is not fully understood, and its effect on intestinal epithelial cells remains unclear. Here, we investigated the effects of AM on junctional molecules in primary-cultured murine intestinal epithelial cells and discovered that AM upregulates claudin-4 expression. In a mouse model of dextran sulfate sodium-induced colitis, AM administration also enhanced claudin-4 expression and accelerated mucosal regeneration. Furthermore, AM reversed TNFα-mediated downregulation of claudin-4 and loss of cell–cell adhesion of the HCT116 human intestinal epithelial cell line in vitro. These results indicate that AM may enhance intestinal epithelial integrity by upregulating claudin-4 expression.
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WS8-9. 生物学的製剤抵抗性クローン病を対象とした多施設共同二重盲検アドレノメデュリンPhase 2a医師主導治験 Reviewed
芦塚伸也、北俊弘、北村和雄
日本消化器 120 ( suppl-1 ) A192 - A192 2023
Publishing type：Research paper (scientific journal)
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追悼 松尾壽之先生 Reviewed
北村和雄
宮崎大学医学科同窓会発行 篠懸 33 35 - 36 2022.12
Publishing type：Research paper (scientific journal)
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【消化管から全身を診る!～消化管ホルモンや神経ペプチドは内科治療の中心になる?～】アドレノメデュリンの消化管運動や炎症への役割(解説) Reviewed
芦塚伸也、北村和雄
消化器病学サイエンス 6 ( 3 ) 167 - 172 2022.9
Publishing type：Research paper (scientific journal)
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消化管ホルモンの最前線~消化管ホルモンから全身を診る~ Reviewed
猿田雅之、坂本昌也、鈴木秀和、北村和雄
消化器病学サイエンス 6 ( 3 ) 133 - 141 2022.9
Publishing type：Research paper (scientific journal)
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In Vivo Wide-Field and Two-Photon Calcium Imaging from a Mouse using a Large Cranial Window Reviewed
Manita S., Shigetomi E., Bito H., Koizumi S., Kitamura K.
Journal of Visualized Experiments 2022 ( 186 ) 2022.8
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Journal of Visualized Experiments
Wide-field calcium imaging from the mouse's neocortex allows one to observe cortexwide neural activity related to various brain functions. On the other hand, twophoton imaging can resolve the activity of local neural circuits at the single-cell level. It is critical to make a large cranial window to perform multiple-scale analysis using both imaging techniques in the same mouse. To achieve this, one must remove a large section of the skull and cover the exposed cortical surface with transparent materials. Previously, glass skulls and polymer-based cranial windows have been developed for this purpose, but these materials are not easily fabricated. The present protocol describes a simple method for making a large cranial window consisting of commercially available polyvinylidene chloride (PVDC) wrapping film, a transparent silicone plug, and a cover glass. For imaging the dorsal surface of an entire hemisphere, the window size was approximately 6 x 3 mm2. Severe brain vibrations were not observed regardless of such a large window. Importantly, the condition of the brain surface did not deteriorate for more than one month. Wide-field imaging of a mouse expressing a genetically-encoded calcium indicator (GECI), GCaMP6f, specifically in astrocytes, revealed synchronized responses in a few millimeters. Twophoton imaging of the same mouse showed prominent calcium responses in individual astrocytes over several seconds. Furthermore, a thin layer of an adeno-associated virus was applied to the PVDC film and successfully expressed GECI in cortical neurons over the cranial window. This technique is reliable and cost-effective for making a large cranial window and facilitates the investigation of the neural and glial dynamics and their interactions during behavior at the macroscopic and microscopic levels.
DOI： 10.3791/64224