Papers - Ito, Hiroshi

Novel axonal projection from the caudal end of the ventrolateral medulla to the intermediolateral cell column

Iigaya, K., Kumagai, H., Onimaru, H., Kawai, A., Oshima, N., Onami, T., Takimoto, C., Kamayachi, T., Hayashi, K., Saruta, T. and Itoh, H.

Am J Physiol Regul Integr Comp Physiol 292 ( 2 ) R927 - 36 2007.02

ISSN  0363-6119

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We used an optical imaging technique to investigate whether axons of neurons in the caudal end of the ventrolateral medulla (CeVLM), as well as axons of neurons in the rostral ventrolateral medulla (RVLM), project to neurons in the intermediolateral cell column (IML) of the spinal cord. Brain stem-spinal cord preparations from neonatal normotensive Wistar-Kyoto and spontaneously hypertensive rats were stained with a voltage-sensitive dye, and responses to electrical stimulation of the IML at the Th2 level were detected as changes in fluorescence intensity with an optical imaging apparatus (MiCAM-01). The results were as follows: 1) depolarizing responses to IML stimulation during low-Ca high-Mg superfusion were detected on the ventral surface of the medulla at the level of the CeVLM, as well as at the level of the RVLM, 2) depolarizing responses were also detected on cross sections at the level of the CeVLM, and they had a latency of 24.0 +/- 5.5 (SD) ms, 3) antidromic action potentials in response to IML stimulation were demonstrated in the CeVLM neurons where optical images were detected, and 4) glutamate application to the CeVLM increased the frequency of excitatory postsynaptic potentials (EPSPs) and induced depolarization of the IML neurons. The optical imaging findings suggested a novel axonal and functional projection from neurons in the CeVLM to the IML. The increase in EPSPs of the IML neurons in response to glutamate application suggests that the CeVLM participates in the regulation of sympathetic nerve activity and blood pressure and may correspond to the caudal pressor area.

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Developmental activity of the renin-angiotensin system during the "critical period" modulates later L-NAME-induced hypertension and renal injury

Ishiguro, K., Sasamura, H., Sakamaki, Y., Itoh, H. and Saruta, T.

Hypertens Res 30 ( 1 ) 63 - 75 2007.01

ISSN  0916-9636

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The incidence of hypertension and hypertensive renal disease is increasing worldwide, and new strategies to prevent these diseases need to be investigated. The aims of this study were 1) to examine if transient exposure to an angiotensin receptor blocker (ARB) during an early period in hypertension development confers protection against subsequent worsening of hypertension and renal injury induced by the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME), and 2) conversely, to examine the effects of transient exposure to angiotensin II (Ang II) during the same period. First, spontaneously hypertensive rats (SHR) were treated transiently from age 3 to 10 weeks with an ARB (candesartan cilexetil), a calcium channel antagonist or a vasodilator, then taken off treatment for 2 months. Administration of L-NAME at age 18 weeks caused severe hypertension and renal injury. However, the rats that had been exposed to the ARB not only had a lower blood pressure, but also failed to show signs of renal injury or increase of oxidative stress. Furthermore, the elevation of components of the renin-angiotensin-aldosterone system was also suppressed in these rats. In the second study, Wistar-Kyoto rats (WKY) and SHR were exposed to Ang II from age 4 to 8 weeks. The follow-up showed that the blood pressures in the WKY remained elevated compared to controls, while the SHR had heightened increases in blood pressure, renal renin mRNA, and urinary 8-hyroxydeoxyguanosine after L-NAME administration. Together, these experiments demonstrate that transient treatment of rats during an early phase in the development of hypertension with an ARB suppresses the renin-angiotensin-aldosterone system and confers long-term protection against subsequent L-NAME-induced renal injury and increases in renal oxidative stress. Conversely, developmental exposure to Ang II during this "critical" period had the opposite effect, predisposing rats to higher blood pressure, renal injury, and oxidative stress after L-NAME administration.

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Regression of Nephropathy Developed in Diabetes by (Pro)rennin Receptor Blockade

Hidena Takahashi, Atsuhiro Ichihara, Yuki Kaneshiro, Kenta Inomata, Mariyo Sakoda, Tomoko Takemitsu, Akira Nishiyama, Itoh Hiroshi

J Am Soc Nephrol 18   2054-2061 2007

Research paper (scientific journal), Joint Work

Coactivation of the N-terminal transactivation of mineralocorticoid receptor by Ubc9

K. Yokota, H. Shibata, I. Kurihara, S. Kobayashi, N. Suda, A. Murai-Takeda, I. Saito, H. Kitagawa, S. Kato, T. Saruta, Itoh Hiroshi

J Biol Chem 282   1998-2010 2007

Research paper (scientific journal), Joint Work

Novel axonal projection from the caudal end of the ventrolateral medulla to the intermediolateral cell column

K. Iigaya, H. Kumagai, H. Onimaru, A. Kawai, N. Ohshima, T. Onami, C. Takimoto, T. Kamayachi, K. Hayashi, T. Saruta, Itoh Hiroshi

Am. J. Physiol. Regul Integr Comp Physiol  ( 292 ) 927-936 2007

Research paper (scientific journal), Joint Work

Role of nonproteolytically activated prorenin in pathologic, but not physiologic, retinal neovascularization

S. Satofuka, A. Ichihara, N. Nagai, T. Koto, H. Shinoda, K. Noda, Y. Ozawa, M. Inoue, K. Tsubota, Itoh Hiroshi, Y. Oike, S. Ishida

Investigative Ophthalmology & Visual Science  ( 48 ) 422-429 2007

Research paper (scientific journal), Joint Work

Add-on amlodipine improves arterial function and structure in hypertensive patients treated with an angiotensin receptor blocker

A. Ichihara, Y. Kaneshiro, M. Sakoda, T. Takemitsu, Itoh Hiroshi

J. Cardiovasc. Pharmacol  ( 49 ) 161-166 2007

Research paper (scientific journal), Joint Work

Developmental Activity of the Renin-Angiotensin System during the “Critical Period” Modulates Later L-NAME-Induced Hypertension and Renal Injury

Kimiko Ishiguro, Hiroyuki Sasamura, Yusuke Sakamaki, Itoh Hiroshi, Takao Saruta

Hypertens Res 30 ( 1 ) 63-75 2007

Research paper (scientific journal), Joint Work

Adrenomedullin/cyclic AMP pathway induces Notch activation and differentiation of arterial endothelial cells from vascular progenitors

Yurugi-Kobayashi, T., Itoh, H., Schroeder, T., Nakano, A., Narazaki, G., Kita, F., Yanagi, K., Hiraoka-Kanie, M., Inoue, E., Ara, T., Nagasawa, T., Just, U., Nakao, K., Nishikawa, S. and Yamashita, J. K.

Arterioscler Thromb Vasc Biol 26 ( 9 ) 1977 - 84 2006.09

ISSN  1079-5642

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OBJECTIVE: The acquisition of arterial or venous identity is highlighted in vascular development. Previously, we have reported an embryonic stem (ES) cell differentiation system that exhibits early vascular development using vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2)-positive cells as common vascular progenitors. In this study, we constructively induced differentiation of arterial and venous endothelial cells (ECs) in vitro to elucidate molecular mechanisms of arterial-venous specification. METHODS AND RESULTS: ECs were induced from VEGFR2+ progenitor cells with various conditions. VEGF was essential to induce ECs. Addition of 8bromo-cAMP or adrenomedullin (AM), an endogenous ligand-elevating cAMP, enhanced VEGF-induced EC differentiation. Whereas VEGF alone mainly induced venous ECs, 8bromo-cAMP (or AM) with VEGF supported substantial induction of arterial ECs. Stimulation of cAMP pathway induced Notch signal activation in ECs. The arterializing effect of VEGF and cAMP was abolished in recombination recognition sequence binding protein at the Jkappa site deficient ES cells lacking Notch signal activation or in ES cells treated with gamma-secretase inhibitor. Nevertheless, forced Notch activation by the constitutively active Notch1 alone did not induce arterial ECs. CONCLUSIONS: Adrenomedullin/cAMP is a novel signaling pathway to activate Notch signaling in differentiating ECs. Coordinated signaling of VEGF, Notch, and cAMP is required to induce arterial ECs from vascular progenitors.

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[PPARgamma]

Itoh, H.

Nihon Rinsho 64 Suppl 5   182 - 91 2006.07

ISSN  0047-1852

[Idiopathic hyperaldosteronism (IHA)]

Miyashita, K., Itoh, H. and Nakao, K.

Nihon Rinsho Suppl 1   624 - 7 2006.05

ISSN  0047-1852

[ACTH-independent macronodular adrenal hyperplasia]

Miyashita, K., Itoh, H. and Nakao, K.

Nihon Rinsho Suppl 1   614 - 7 2006.05

ISSN  0047-1852

The neuroprotective and vasculo-neuro-regenerative roles of adrenomedullin in ischemic brain and its therapeutic potential

Miyashita, K., Itoh, H., Arai, H., Suganami, T., Sawada, N., Fukunaga, Y., Sone, M., Yamahara, K., Yurugi-Kobayashi, T., Park, K., Oyamada, N., Sawada, N., Taura, D., Tsujimoto, H., Chao, T. H., Tamura, N., Mukoyama, M. and Nakao, K.

Endocrinology 147 ( 4 ) 1642 - 53 2006.04

ISSN  0013-7227

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Adrenomedullin (AM) is a vasodilating hormone secreted mainly from vascular wall, and its expression is markedly enhanced after stroke. We have revealed that AM promotes not only vasodilation but also vascular regeneration. In this study, we focused on the roles of AM in the ischemic brain and examined its therapeutic potential. We developed novel AM-transgenic (AM-Tg) mice that overproduce AM in the liver and performed middle cerebral artery occlusion for 20 min (20m-MCAO) to examine the effects of AM on degenerative or regenerative processes in ischemic brain. The infarct area and gliosis after 20m-MCAO was reduced in AM-Tg mice in association with suppression of leukocyte infiltration, oxidative stress, and apoptosis in the ischemic core. In addition, vascular regeneration and subsequent neurogenesis were enhanced in AM-Tg mice, preceded by increase in mobilization of CD34(+) mononuclear cells, which can differentiate into endothelial cells. The vasculo-neuro-regenerative actions observed in AM-Tg mice in combination with neuroprotection resulted in improved recovery of motor function. Brain edema was also significantly reduced in AM-Tg mice via suppression of vascular permeability. In vitro, AM exerted direct antiapoptotic and neurogenic actions on neuronal cells. Exogenous administration of AM in mice after 20m-MCAO also reduced the infarct area, and promoted vascular regeneration and functional recovery. In summary, this study suggests the neuroprotective and vasculo-neuro-regenerative roles of AM and provides basis for a new strategy to rescue ischemic brain through its multiple hormonal actions.

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Expression of the adrenomedullin gene in adipose tissue

Nambu, T., Arai, H., Komatsu, Y., Yasoda, A., Moriyama, K., Kanamoto, N., Itoh, H. and Nakao, K.

Regul Pept 132 ( 1-3 ) 17 - 22 2005.12

ISSN  0167-0115

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Adrenomedullin (AM) is a potent vasodilating peptide originally isolated from human pheochromocytoma cells. This report concerns the expression and secretion of AM from adipose tissue. Northern blot analysis demonstrated marked expression of AM mRNA in mouse adipose tissue. Expression levels in adipose tissues were 2.5-3.2 times higher than in the kidney. AM mRNA level in mature adipocytes was 7.3 times higher than in the stroma-vascular fraction of adipose tissue. In mature adipocyte culture, time-dependent increase of AM peptide concentration in the culture medium was detected. AM expression was also detected in human subcutaneous adipose tissue. Adipose AM expression significantly increased in obesity mouse model, high-fat diet fed mice and ob/ob mice. These results suggest that adipose tissue, especially mature adipocytes, is major source of AM in the body, and that adipocyte-derived AM plays a pathophysiological role in obesity.

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Papillary thyroid carcinoma without metastases manifesting as an autonomously functioning thyroid nodule

Majima, T., Doi, K., Komatsu, Y., Itoh, H., Fukao, A., Shigemoto, M., Takagi, C., Corners, J., Mizuta, N., Kato, R. and Nakao, K.

Endocr J 52 ( 3 ) 309 - 16 2005.06

ISSN  0918-8959

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A 59-year-old woman with papillary thyroid carcinoma inside of an autonomously functioning thyroid nodule is described in this report. The patient was referred to our clinic because of rapid weight loss and swelling on the left side of the neck. Ultrasonography of the thyroid demonstrated a nonhomogeneous nodule in the lower part of an enlarged left lobe. Both 99mTc and 123I thyroid scintigraphic imaging showed a hot area corresponding to the nodule with lower uptake in the remaining thyroid tissue. Histopathological examination of the nodule revealed papillary adenocarcinoma, and the immunohistochemistry proved weak but positive staining for triiodothyronine and thyroxine. Based on these findings, the nodule was diagnosed as a functioning papillary adenocarcinoma. Although thyroid carcinoma manifesting as a hot nodule on the radionuclide isotope scan is an extremely rare occurrence, the current case is clinically important because it suggests that the diagnosis of a hot nodule cannot always rule out thyroid carcinoma in the nodule, and that even a hot nodule requires careful management so that the malignancy is not overlooked.

Analysis of rat insulin II promoter-ghrelin transgenic mice and rat glucagon promoter-ghrelin transgenic mice

Iwakura, H., Hosoda, K., Son, C., Fujikura, J., Tomita, T., Noguchi, M., Ariyasu, H., Takaya, K., Masuzaki, H., Ogawa, Y., Hayashi, T., Inoue, G., Akamizu, T., Hosoda, H., Kojima, M., Itoh, H., Toyokuni, S., Kangawa, K. and Nakao, K.

J Biol Chem 280 ( 15 ) 15247 - 56 2005.04

ISSN  0021-9258

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We developed and analyzed two types of transgenic mice: rat insulin II promoter-ghrelin transgenic (RIP-G Tg) and rat glucagon promoter-ghrelin transgenic mice (RGP-G Tg). The pancreatic tissue ghrelin concentration measured by C-terminal radioimmunoassay (RIA) and plasma desacyl ghrelin concentration of RIP-G Tg were about 1000 and 3.4 times higher than those of nontransgenic littermates, respectively. The pancreatic tissue n-octanoylated ghrelin concentration measured by N-terminal RIA and plasma n-octanoylated ghrelin concentration of RIP-G Tg were not distinguishable from those of nontransgenic littermates. RIP-G Tg showed suppression of glucose-stimulated insulin secretion. Arginine-stimulated insulin secretion, pancreatic insulin mRNA and peptide levels, beta cell mass, islet architecture, and GLUT2 and PDX-1 immunoreactivity in RIP-G Tg pancreas were not significantly different from those of nontransgenic littermates. Islet batch incubation study did not show suppression of insulin secretion of RIP-G Tg in vitro. The insulin tolerance test showed lower tendency of blood glucose levels in RIP-G Tg. Taking lower tendency of triglyceride level of RIP-G Tg into consideration, these results may indicate that the suppression of insulin secretion is likely due to the effect of desacyl ghrelin on insulin sensitivity. RGP-G Tg, in which the pancreatic tissue ghrelin concentration measured by C-RIA was about 50 times higher than that of nontransgenic littermates, showed no significant changes in insulin secretion, glucose metabolism, islet mass, and islet architecture. The present study raises the possibility that desacyl ghrelin may have influence on glucose metabolism.

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Angiotensin II suppresses growth arrest specific homeobox (Gax) expression via redox-sensitive mitogen-activated protein kinase (MAPK)

Saito, T., Itoh, H., Yamashita, J., Doi, K., Chun, T. H., Tanaka, T., Inoue, M., Masatsugu, K., Fukunaga, Y., Sawada, N., Sakaguchi, S., Arai, H., Tojo, K., Tajima, N., Hosoya, T. and Nakao, K.

Regul Pept 127 ( 1-3 ) 159 - 67 2005.04

ISSN  0167-0115

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Oxidative stress is known to be involved in growth control of vascular smooth muscle cells (VSMCs). We and others have demonstrated that angiotensin II (Ang II) has an important role in vascular remodeling. Several reports suggested that VSMC growth induced by Ang II was elicited by oxidative stress. Gax, growth arrest-specific homeobox is a homeobox gene expressed in the cardiovascular system. Over expression of Gax is demonstrated to inhibit VSMC growth. We previously reported that Ang II down-regulated Gax expression. To address the regulatory mechanism of Gax, we investigated the significance of oxidative stress in Ang II-induced suppression of Gax expression. We further examined the involvement of mitogen-activated protein kinases (MAPKs), which is crucial for cell growth and has shown to be activated by oxidative stress, on the regulation of Gax expression by Ang II. Ang II markedly augmented intracellular H2O2 production which was decreased by pretreatment with N-acetylcystein (NAC), an anti-oxidant. Ang II and H2O2 decreased Gax expression dose-dependently and these effects were blocked by administration of both NAC and pyrrolidine dithiocarbamate (PDTC), another anti-oxidant. Ang II and H2O2 induced marked activation of extracellular signal-responsive kinase1/2 (ERK1/2), which was blocked by NAC. Ang II and H2O2 also activated p38MAPK, and they were blocked by pre-treatment with NAC. However, the level of activated p38MAPK was quite low in comparison with ERK1/2. Ang II- or H2O2 -induced Gax down-regulation was significantly inhibited by PD98059, an ERK1/2 inhibitor but not SB203580, a p38MAPK inhibitor. The present results demonstrated the significance of regulation of Gax expression by redox-sensitive ERK1/2 activation.

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[PPARs and hypertension]

Itoh, H.

Nihon Rinsho 63 ( 4 ) 631 - 42 2005.04

ISSN  0047-1852

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PPARs (peroxisome proliferator-activated receptors) alpha, delta and gamma are expressed in adipocytes, skeletal myocytes and hepatocytes and also in endothelial cells, vascular smooth muscle cells and monocytes/macrophages, in distinct distributions. They are critically involved in the pathophysiology of obesity, diabetes, hyperlipidemia and hypertension, the complex of which is recognized as "metabolic syndrome", as well as, of their vascular complications. In addition to modulation of insulin sensitivity, PPARs can regulate oxidative stress and local production of various vasoactive substances in blood vessels, and thus control vascular tone and remodeling as one of the determinants of hypertension.

[Renin-angiotensin system and metabolic domino]

Itoh, H.

Nihon Rinsho 63 Suppl 3   180 - 7 2005.03

ISSN  0047-1852

Therapeutic potential of thiazolidinediones in activation of peroxisome proliferator-activated receptor gamma for monocyte recruitment and endothelial regeneration

Tanaka, T., Fukunaga, Y., Itoh, H., Doi, K., Yamashita, J., Chun, T. H., Inoue, M., Masatsugu, K., Saito, T., Sawada, N., Sakaguchi, S., Arai, H. and Nakao, K.

Eur J Pharmacol 508 ( 1-3 ) 255 - 65 2005.01

ISSN  0014-2999

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Thiazolidinediones, a new class of antidiabetic drugs that increase insulin sensitivity, have been shown to be ligands for peroxisome proliferator-activated receptor gamma (PPARgamma). Recent studies demonstrating that PPARgamma occurs in macrophages have focused attention on its role in macrophage functions. In this study, we investigated the effect of thiazolidinediones on monocyte proliferation and migration in vitro and the mechanisms involved. In addition, we examined the therapeutic potentials of thiazolidinediones for injured atherosclerotic lesions. Troglitazone and pioglitazone, the two thiazolidinediones, as well as 15-deoxy-delta12,14-prostaglandin J2 inhibited in a dose-dependent manner the serum-induced proliferation of THP-1 (human monocytic leukemia cells) and of U937 (human monoblastic leukemia cells), which permanently express PPARgamma. These ligands for PPARgamma also significantly inhibited migration of THP-1 induced by monocyte chemoattractant protein-1 (MCP-1). Troglitazone and 15-deoxy-delta12,14-prostaglandin J2 significantly suppressed the mRNA expression of the MCP family-specific receptor CCR2 (chemokine CCR2 receptor) in THP-1 at the transcriptional level. Furthermore, troglitazone significantly inhibited MCP-1 binding to THP-1. Oral administration of troglitazone to Watanabe heritable hyperlipidemic (WHHL) rabbits after balloon injury suppressed acute recruitment of monocytes/macrophages and accelerated re-endothelialization. These results suggest that thiazolidinediones have therapeutic potential for the treatment of diabetic vascular complications.

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