Kazuhiro Takahashi

Tohoku University, Miyagi, Japan

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Publications (192)643.7 Total impact

  • Kazuhiro Takahashi · Koji Ohba · Kiriko Kaneko ·
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    ABSTRACT: Biologically active peptides are widely expressed throughout in human bodies. For example, endothelin-1 and adrenomedullin are expressed in almost all types of cells, including neurons, glial cells, fibroblasts, macrophages, cardiomyocytes, vascular endothelial cells, epithelial cells and cancer cells of various origins. Expression of both these peptides is induced by stimuli, such as hypoxia and inflammatory cytokines. They have a variety of biological functions, such as effects on brain function, hormone secretion, the cardiovascular system and cell proliferation. By contrast, orexins (hypocretins) and melanin-concentrating hormone (MCH) are specifically expressed in the hypothalamus, particularly in the lateral hypothalamus, although very low concentrations of these peptides are found in the peripheral tissues. Orexins and MCH play coordinated, but distinct physiological roles in the regulation of sleep-wake cycle, appetite, emotion and other brain functions. The cardiovascular system is regulated by cardiovascular peptides, such as natriuretic peptides, endothelins and angiotensin II. The renin-angiotensin system (RAS) is one of the most classical regulatory systems on blood pressure, electrolytes and kidney. (Pro)renin receptor is a novel member of the RAS and may be related to the pathophysiology of microvascular complications of hypertension and diabetes mellitus. Moreover, (pro)renin receptor forms a functional complex with vacuolar-type H(+)-ATPase, which plays an important physiological role in maintaining the acidic environment of intracellular compartments including secretory vesicles. Perhaps, the complex of (pro)renin receptor and vacuolar-type H(+)-ATPase may be important for the post-translational processing and secretion of many biologically active peptides. Copyright © 2015. Published by Elsevier Inc.
    Peptides 04/2015; 72. DOI:10.1016/j.peptides.2015.04.004 · 2.62 Impact Factor
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    ABSTRACT: A functional receptor for renin and prorenin ((P)RR) was identified as a new component of the renin-angiotensin system. The precise localization of (P)RR in the kidney has not been clarified. The present study was designed to determine the localization of (P)RR in the rat nephron and to investigate the regulation of renal (P)RR expression by high salt (HS) intake. (P)RR mRNA levels in the kidney sections and isolated nephron segments were examined using reverse transcription and polymerase chain reaction (RT-PCR), and (P)RR protein levels were examined by immunoblot and immunohistochemical analyses. Renal (P)RR mRNA and protein levels in rats fed a HS diet for 4 weeks were also compared with those fed a normal salt diet. (P)RR mRNA was expressed in various nephron segments of the cortex and medulla; glomeruli (Glm), proximal tubules (PT), thick ascending limbs (TAL) and collecting ducts (CD). (P)RR protein was highly expressed in the PT, medullary TAL (MTAL) and inner medullary CD (IMCD), and lowly in the preglomerular arterioles (Art) and Glm. HS intake increased (P)RR protein levels in the Glm, PT and tubules of medullary rays. These results indicated that (P)RR is expressed throughout various nephron segments and Art, and that (P)RR protein is expressed predominantly in the PT, MTAL and IMCD. HS intake appears to upregulate the (P)RR expression in the Glm, PT and tubules of medullary rays, suggesting that (P)RR may be involved in the regulation of renal function and HS-induced disorders. Copyright © 2014. Published by Elsevier Inc.
    Peptides 12/2014; 63. DOI:10.1016/j.peptides.2014.12.007 · 2.62 Impact Factor
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    ABSTRACT: Bromocriptine, a potent D2-dopamine agonist, suppresses growth hormone (GH) secretion in most patients with acromegaly and has been approved for the treatment of acromegaly. Here we report a patient with acromegaly who showed increased GH secretion after administration of bromocriptine. A 70-year-old man with acromegalic manifestation was admitted to our hospital because of a pituitary tumor invading to the right cavernous sinus detected by brain magnetic resonance imaging. Serum GH and insulin-like growth factor-I (IGF-I) levels were elevated in several occasions (GH: 15.0-51.7 ng/mL, reference range: < 2.47 ng/mL; and IGF-I: 776-856 ng/mL, reference range: 57-175 ng/mL). Effect of bromocriptine on serum GH levels was then studied because pre-operative treatment with a D2-dopamine agonist was planned in order to reduce the tumor size and serum GH levels before surgery. After oral administration of 2.5 mg of bromocriptine, serum GH levels were unexpectedly increased from 30.7 ng/mL to 189 ng/mL, despite the fact that the levels of prolactin (PRL) were decreased from 4.2 ng/mL to 0.6 ng/mL. By contrast, serum GH levels were decreased by a somatostatin analogue, octreotide. Transsphenoidal surgery of the pituitary tumor was performed after treatment of octreotide. Histological analysis and immunohistochemistry revealed a GH-producing pituitary adenoma positive for D2-dopamine receptor. This case of acromegaly suggests that the preliminary test with a single administration of a short-acting D2-dopamine agonist, bromocriptine, is mandatory before the long-term therapy with a D2-dopamine agonist in patients with GH-secreting pituitary tumors.
    The Tohoku Journal of Experimental Medicine 10/2014; 234(2):129-135. DOI:10.1620/tjem.234.129 · 1.35 Impact Factor
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    ABSTRACT: TSH is the important regulator of thyroid function but detailed molecular mechanisms have not been clarified. We first generated the iodine deficient (ID) rat in which goiter is induced by accelerated endogenous TSH secretion. The result of microarray analysis demonstrated markedly increased levels of adrenomedullin 2/intermedin (AM2/IMD) expression in the ID rat thyroid. AM2/IMD is a potent vasodilator. AM2/IMD mRNA expression was induced by TSH in a rat thyroid follicular cell line FRTL-5. Immunohistochemical analysis in human normal and Graves' disease thyroid revealed that AM2/IMD immunoreactivity was detected in follicular cells and more pronounced in Graves' disease. These results indicated that TSH induced AM2/IMD expression in the rat thyroid gland and it could locally work as a potent vasodilator, resulting in the expansion of thyroid inter-follicular capillaries. AM2/IMD could also contribute to facilitate thyroid hormone synthesis possibly via vasodilation effects and/or cAMP stimulating effects in the human thyroid gland.
    Molecular and Cellular Endocrinology 09/2014; 395(1). DOI:10.1016/j.mce.2014.07.008 · 4.41 Impact Factor
  • Tsuguo Nishijima · Kazuki Tajima · Kazuhiro Takahashi · Shigeru Sakurai ·
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    ABSTRACT: (Pro)renin receptor ((P)RR) is a specific receptor for both renin and its precursor prorenin. (P)RR was shown to be involved in pathophysiology of cardiovascular and renal diseases. Soluble (pro)renin receptor (s(P)RR), which is generated by furin from full length (P)RR, is present in blood. The aim of the present study is to clarify the association of plasma s(P)RR levels and the severity of OSAS. Plasma levels of s(P)RR were measured by ELISA in 58 male patients diagnosed as OSAS based on polysomnography, and 14 age-matched male control subjects. Blood samples were obtained at 6:00 a.m. just after overnight polysomnography. Plasma s(P)RR levels were significantly higher in patients with OSAS (9.0 ± 2.0 ng/mL, mean ± SD) than in control subjects (7.4 ± 1.5 ng/mL) (P = 0.0026). Plasma s(P)RR levels showed a significant negative correlation with % stage rapid eye movement (REM) sleep (r = -0.377, p < 0.005), and significant positive correlations with % stage 1 (r = 0.374, p < 0.005), arousal index (r = 0.341, p < 0.01), apnea hypopnea index (AHI) (r = 0.352, p < 0.01) and desaturation index (r = 0.302, p < 0. 05). In 12 OSAS patients with AHI ≥20, plasma levels of s(P)RR were studied after 3-month treatment with nasal continuous positive airway pressure (nCPAP). Plasma s(P)RR levels were significantly decreased after the nCPAP treatment (p = 0.0016). The present study has shown for the first time elevated plasma s(P)RR levels in patients with OSAS. Plasma s(P)RR levels were associated with the severity of OSAS. Soluble (P)RR may serve as a plasma marker reflecting the severity of OSAS.
    Peptides 06/2014; 56. DOI:10.1016/j.peptides.2014.03.008 · 2.62 Impact Factor
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    ABSTRACT: (Pro)renin receptor ((P)RR) is a specific receptor for renin and prorenin. The aim of the presentstudy is to clarify expression of (P)RR and pathophysiological roles of (P)RR in human breastcarcinomas. (P)RR expression was studied in 69 clinical cases of breast carcinoma by immunohistochemistry.Effects of (P)RR on cell proliferation were examined in cultured human breast carcinomacells using (P)RR specific small interference RNA. Immunohistochemistry showed that(P)RR immunoreactivity was detected in the breast carcinoma cells in 50 of 69 cases of breastcarcinoma (72%). The analysis on association between (P)RR immunoreactivity and clinicopathologicalparameters showed that the number of (P)RR positive cases was significantly greater inKi-67 (a cell proliferation marker) ≥ 10% group than in Ki-67 < 10% group (P = 0.02). (P)RR wasexpressed in 4 types of human breast carcinoma cell lines. (P)RR specific small interference RNAinhibited proliferation of both MCF-7 (ERα positive) and SK-BR-3 (ERα negative) cells. Thepresent study has shown, for the first time, the expression of (P)RR in human breast carcinomatissues and cultured breast carcinoma cell lines. These findings have raised the possibility that theblockade of the (P)RR signaling may be a novel therapeutic strategy against breast carcinomas.
    Biomedical Research 04/2014; 35(2):117-26. DOI:10.2220/biomedres.35.117 · 1.14 Impact Factor
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    ABSTRACT: Aberrant expression of gonadotropin-releasing hormone receptor (GnRHR) has been reported in human adrenal tissues including aldosterone-producing adenoma (APA). However, the details of its expression and functional role in adrenals are still not clear. In this study, quantitative RT-PCR analysis revealed the mean level of GnRHR mRNA was significantly higher in APAs than in human normal adrenal (NA) (P=0.004). GnRHR protein expression was detected in human NA and neoplastic adrenal tissues. In H295R cells transfected with GnRHR, treatment with GnRH resulted in a concentration-dependent increase in CYP11B2 reporter activity. Chronic activation of GnRHR with GnRH (100 nM), in a cell line with doxycycline-inducible GnRHR (H295R-TR/GnRHR), increased CYP11B2 expression and aldosterone production. These agonistic effects were inhibited by blockers for the calcium (Ca(2+)) signaling pathway, KN93 and calmidazolium. These results suggest GnRH, through heterotopic expression of its receptor, may be a potential regulator of CYP11B2 expression levels in some cases of APA.
    Molecular and Cellular Endocrinology 01/2014; 384(1). DOI:10.1016/j.mce.2014.01.016 · 4.41 Impact Factor
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    Life Sciences 12/2013; 93(25-26):e10. DOI:10.1016/j.lfs.2013.12.054 · 2.70 Impact Factor
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    ABSTRACT: (Pro)renin receptor ((P)RR) is a specific receptor for renin and prorenin. The aim of the present study is to clarify expression and possible pathophysiological roles of (P)RR in aldosterone-producing adenomas (APAs) and other adrenal tumors. Expression of (P)RR was studied by immunocytochemistry, western blot analysis and real-time RT-PCR in adrenal tumor tissues obtained at surgery. Immunocytochemistry showed that (P)RR was expressed in normal adrenal glands and tumor tissues of adrenocortical tumors including APAs. In the normal adrenal glands, positive (P)RR immunostaining was observed in both adrenal cortex and medulla, with higher (P)RR immunostaining observed in zona glomerulosa and zona reticularis. Positive (P)RR immunostaining was also observed in the adrenocortical tumors, with elevated (P)RR immunostaining found in APAs, particularly in compact cells. By contrast, no apparent (P)RR immunostaining was observed in pheochromocytomas. Western blot analysis showed a band of (P)RR protein in normal adrenal glands and adrenocortical tumors at the position of 35kDa. The relative expression levels of (P)RR protein were higher in tumor tissues of APAs than in attached non-neoplastic adrenal tissues of APAs. Real-time RT-PCR showed that expression levels of (P)RR mRNA were significantly increased in tumor tissues of APAs compared with other adrenal tumor tissues and attached non-neoplastic adrenal tissues of APAs. The present study has shown for the first time that expression of (P)RR is elevated in tumor tissues of APAs, raising the possibility that (P)RR may play pathophysiological roles in APAs, such as aldosterone secretion and cell proliferation.
    Peptides 09/2013; 49. DOI:10.1016/j.peptides.2013.08.022 · 2.62 Impact Factor
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    ABSTRACT: Pendred syndrome is an autosomal recessive disorder characterized by sensorineural deafness, a partial defect in iodide organification, and dyshormonogenetic goiter. Several cases of Pendred syndrome with follicular thyroid carcinomas were reported previously. Here we report identical twin patients with Pendred syndrome, who had thyroid tumors with distinct histopathological findings. 34-year-old identical twins with congenital deafness and goiter were referred to our hospital with complaint of neck discomfort. The genetic testing showed that these twin patients were compound heterozygotes carrying the same two mutations in the Pendred's syndrome (PDS / SLC26A4) gene (c2168A>G and ins2110GCTGG), which confirmed the diagnoses of Pendred syndrome. They underwent thyroidectomy. Histological examination of the thyroid tumors resected from these twin patients revealed follicular variant of papillary thyroid carcinoma, and diffuse and nodular goiter without any evidence of malignancy, respectively. To our knowledge, the former is the first case of follicular variant of papillary thyroid carcinoma in Pendred Syndrome.
    Endocrine Journal 03/2013; 60(6). DOI:10.1507/endocrj.EJ12-0396 · 2.00 Impact Factor
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    ABSTRACT: Expression of (pro)renin receptor ((P)RR), a specific receptor for renin and prorenin, was studied in rat pituitary gland. In situ hybridization showed that cells expressing (P)RR mRNA were widely distributed in the anterior lobe and intermediate lobe of the pituitary gland. Double-staining using in situ hybridization for (P)RR mRNA and immunohistochemistry for the pituitary hormones showed that (P)RR mRNA was expressed in most of the GH cells and ACTH cells in the anterior lobe. (P)RR mRNA was also expressed in a few prolactin cells and TSH cells, but not in LH cells. The present study has shown for the first time the distribution of (P)RR mRNA expressing cells in the rat pituitary gland. These findings suggest that (P)RR plays physiological roles in the pituitary gland, such as the modulation of the pituitary hormone secretion.
    Acta histochemica et cytochemica official journal of the Japan Society of Histochemistry and Cytochemistry 02/2013; 46(1):47-50. DOI:10.1267/ahc.12030 · 1.39 Impact Factor
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    ABSTRACT: The renin-angiotensin system is known to enhance erythropoiesis. (Pro)renin receptor ((P)RR), a specific receptor for renin and prorenin, has recently been identified. However, expression of (P)RR in erythroid cells has not been studied. The aim of the present study is to clarify expression of (P)RR in erythroid cells, and the effects of erythropoietin, angiotensin II, transforming growth factor-β1 (TGF-β1), interferon-γ (IFN-γ) and interleukin-1β (IL-1β) on its expression. Western blot analysis showed that (P)RR protein was expressed in human cultured erythroid cell lines, YN-1 and YN-1-0-A (a clonal variant cell line of YN-1). Erythropoietin (1IU/ml) increased (P)RR mRNA expression levels in YN-1-0-A cells (1.7-fold increase compared with control), but angiotensin II did not. Treatment of YN-1-0-A cells with IFN-γ (10ng/ml) for 48h increased the expression levels of (P)RR protein significantly (1.4-fold increase compared with control), whereas it had no significant effects on expression levels of (P)RR mRNA. Treatment of YN-1-0-A cells with TGF-β1 or IL-1β for 24 or 48h had no significant effects on expression levels of (P)RR. The present study has shown for the first time expression of (P)RR in erythroid cells, raising the possibility that (P)RR may have a role in erythropoiesis and the pathophysiology of certain types of anemia.
    Peptides 07/2012; 37(2):285-9. DOI:10.1016/j.peptides.2012.07.015 · 2.62 Impact Factor
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    Kazuhiro Takahashi ·
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    ABSTRACT: Urocortins are human homologues of urotensin I, a fish corticotropin-releasing-factor- (CRF-) like peptide secreted from the urophysis. There are three urocortins: urocortin 1, urocortin 2, and urocortin 3 in mammals. We have shown that urocortin 1 and urocortin 3 are endogenously synthesized in the myocardial cells of human heart and may act on CRF type 2 receptor (CRFR2) expressed in the heart. Expression levels of urocortin 1 in the heart and plasma urocortin 1 levels are elevated in patients with heart failure. Recent studies have shown that urocortins have various biological actions in the cardiovascular system, such as a vasodilator action, a positive inotropic action, a cardioprotective action against ischemia/reperfusion injury, and suppressive actions against the renin angiotensin system and the sympathetic nervous system. Urocortins and CRFR2 may therefore be a potential therapeutic target for cardiovascular diseases, such as congestive heart failure, hypertension, and myocardial infarction.
    International Journal of Endocrinology 05/2012; 2012(5):395284. DOI:10.1155/2012/395284 · 1.95 Impact Factor

  • Scientific Sessions of High Blood Pressure Research; 11/2011
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    ABSTRACT: GH-producing pituitary adenomas frequently co-produce other certain anterior pituitary hormones, such as prolactin (PRL). In contrast, GH-producing adenomas which express all of corticotropin-releasing factor (CRF), urocorin1 (Ucn1) and urocortin3 (Ucn3) have not been reported. A 39-year-old woman was admitted for evaluation of the pituitary tumor. The diagnosis of acromegaly was confirmed by elevated serum GH and IGF-I levels, and the absence of GH suppression by oral glucose tolerance test. ACTH response to desmopressin (DDAVP) was observed (plasma ACTH levels increased from 13.9 to 50.4 pg/ml at 90 min). Although it is known that ACTH response to DDAVP is considerably useful for the diagnosis of ACTH-dependent Cushing's syndrome, the diagnosis of Cushing's disease was not supported by the criteria. The patient underwent transsphenoidal resection of the pituitary tumor. Immunohistological examination confirmed a GH- and PRL-producing adenoma, whereas ACTH was negative. ACTH response to DDAVP disappeared after tumor removal. To determine the cause of preoperative ACTH response to DDAVP, we examined expression of CRF family peptides and vasopressin V1b receptor in the pituitary adenoma by immunohistochemistry. Immunohistochemistry revealed positive immunostaining for CRF, Ucn1, Ucn3 and vasopressin V1b receptor in the adenoma. These observations raised the possibility that DDAVP caused an ACTH response, perhaps via the paracrine effects of tumor-derived CRF and Ucn1. When ACTH response to DDAVP is observed in patients with pituitary tumor, not only the direct effect of DDAVP on ACTH secretion, but also a possible involvement of CRF and/or urocortins expressed in the pituitary adenoma, should be considered.
    Endocrine Journal 09/2011; 58(12):1029-36. DOI:10.1507/endocrj.EJ11-0038 · 2.00 Impact Factor
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    ABSTRACT: Adrenomedullin 2/intermedin (AM2/IMD) is a novel vasodilator peptide with various effects on the renal function and cardiovascular system. An exonic insertion (I)/deletion (D) polymorphism (rs3840963) may influence generation of AM2/IMD-53, due to its location within the N-terminal sequence. We investigated the association of this polymorphism with blood pressure, renal function and the risk of silent cerebrovascular lesions in a Japanese population recruited from the Ohasama study. We recorded 24 h ambulatory blood pressure (ABP), estimated glomerular filtration rate (eGFR) and proteinuria of 1073 individuals over 40 years of age. Silent cerebrovascular lesions (lacunar infarction and white matter hyperintensity (WMH)) were recorded in 794 individuals over 55 years of age. Chronic kidney disease (CKD) was diagnosed in individuals with proteinuria and/or decreased eGFR ≤60 ml min(-1) per 1.73 m(2). DD carriers, compared with II and ID carriers, displayed significantly higher 24 h ABP (127.4 vs. 122.0 and 122.9 mm Hg, respectively, in systolic ABP, P=0.009; and 74.8 vs. 71.3 and 72.5 mm Hg, respectively, in diastolic ABP, P=0.002), and lower eGFR (75.4 vs. 82.6 and 82.9 ml min(-1) per 1.73 m(2), respectively, P=0.04). DD carriers also had a significantly higher odds ratio (OR) for prevalence of CKD (OR: 2.7, P=0.003), presence of lacunar infarction (OR: 2.4, P=0.01) and WMH (OR: 2.7, P=0.003), compared with II carriers. The AM2/IMD I/D polymorphism is associated with renal dysfunction, blood pressure regulation and asymptomatic cerebrovascular diseases in the Japanese general population.
    Hypertension Research 08/2011; 34(12):1327-32. DOI:10.1038/hr.2011.131 · 2.66 Impact Factor
  • Kazuhiro Takahashi · Ryo Morimoto · Takuo Hirose · Fumitoshi Satoh · Kazuhito Totsune ·
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    ABSTRACT: Adrenomedullin 2/intermedin (AM2/IMD) is a new member of the calcitonin/calcitonin gene-related peptide (CGRP) family. CGRP, adrenomedullin (AM), and AM2/IMD share the receptor system consisting of calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMP). The CRLR/RAMP2 or CRLR/RAMP3 complex forms the AM receptor, whereas the CRLR/RAMP1 forms the CGRP receptor. AM2/IMD binds non-selectively to all three CRLR/RAMP complexes. AM2/IMD has various actions, such as a potent vasodilator action and a protective action against oxidative stress, like AM and CGRP. When administered intracerebroventricularly, AM2/IMD stimulates the sympathetic nervous system and increases blood pressure. In human hypothalamus, AM2/IMD is expressed in the paraventricular and supraoptic nuclei and colocalized with arginine vasopressin. Anterior pituitary cells were diffusely immunostained for AM2/IMD. AM2/IMD stimulates the release of ACTH, prolactin, and oxytocin, but suppresses GH release. Some of these pituitary actions of AM2/IMD have been supposed to be mediated by an unidentified unique receptor for AM2/IMD. In the adrenal gland, immunoreactive (IR)-AM2/IMD and IR-AM were detected in the medulla, while the degree of IR-AM2/IMD and IR-AM in the cortex was relatively weak or undetectable. Furthermore, AM2/IMD and AM were expressed in adrenocortical tumors, such as aldosterone-secreting adenomas, and pheochromocytomas. CRLR and RAMPs are expressed in the hypothalamus, pituitaries, adrenal glands, and adrenal tumors. Thus, AM2/IMD is expressed in every endocrine organ of the hypothalamo-pituitary-adrenal axis together with its receptor. AM2/IMD may act as a neurotransmitter or modulator in the brain and as a paracrine/autocrine regulator in the hypothalamo-pituitary-adrenal axis.
    Journal of Molecular Neuroscience 02/2011; 43(2):182-92. DOI:10.1007/s12031-010-9413-2 · 2.34 Impact Factor
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    ABSTRACT: Recent studies have revealed that (pro)renin receptor ((P)RR), a newly identified member of the renin-angiotensin system, is associated with organ damage that occurs with cardiovascular disease. We investigated the association of genetic polymorphisms in the (P)RR gene with lacunar infarction, white matter hyperintensity and left ventricular hypertrophy (LVH) in a Japanese general population recruited from the Ohasama study, a Japanese cohort study. A total of 779 subjects (men=250 and women=529) were recruited. For the association study, we selected three polymorphisms: -782A>G (rs2968915), intervening sequence (IVS)5+169C>T (rs5918007) and +1513A>G (rs6609080). In women, the prevalence of lacunar infarction and LVH was significantly higher in subjects with the +1513GG genotype than in those with the AA or AG genotypes (lacunar infarction: P=0.01, LVH: P=0.003). Plasma renin activity (PRA) levels in women with the GG genotype were significantly lower than in women with the AA or AG genotypes (P=0.01). Multiple logistic regression analysis adjusted for confounding factors demonstrated that +1513A>G polymorphism was significantly and independently associated with the risk of lacunar infarction (trend P=0.03) and LVH (trend P=0.003). In men, there were no significant differences in lacunar infarction, LVH or PRA levels among the three genotypes. The polymorphism of the (P)RR gene +1513A>G is associated with lacunar infarction and LVH in Japanese women. These results suggest that (P)RR has a role in organ damage in humans.
    Hypertension Research 01/2011; 34(4):530-5. DOI:10.1038/hr.2010.274 · 2.66 Impact Factor
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    ABSTRACT: Histamine and calcitonin gene-related peptide (CGRP) contribute to the pain perception. The aim of the present study is to clarify the interaction of histamine and CGRP in the perception of inflammatory pain. The effects of a histamine H1 receptor antagonist (pyrilamine, i.p.), an H2 receptor antagonist (ranitidine, i.p.) and a CGRP antagonist (CGRP 8-37, i.t.) on the formalininduced pain was studied in rats. Pyrilamine and ranitidine produced a dose-dependent antinociceptive response in the first and the second phases of the formalin test. A single administration of pyrilamine (1 mg/kg, i.p.), ranitidine (10 mg/kg, i.p.) or CGRP 8-37 (10 µg/µL, i.t.) had no significant effects on the pain perception in the second phase. A combination of CGRP 8-37 and pyrilamine or ranitidine at these sub-effective doses, however, showed nociceptive response in the second phase. Moreover, a histamine (i.t.)-induced hyperalgesia was completely prevented by treatment with GGRP 8-37 at this dose. Our findings have raised the possibility that the CGRP system has interaction with histamine in the perception of inflammatory pain.
    Biomedical Research 01/2011; 32(3):195-201. DOI:10.2220/biomedres.32.195 · 1.14 Impact Factor
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    ABSTRACT: Kisspeptins are biologically active cleavage peptides of the KiSS-1 gene products with important roles in the suppression of tumor metastasis and in the reproduction. The aim of the present study is to clarify changes of the expression of kisspeptins and kisspeptin receptor in the kidney with and without chronic renal impairment. 5/6 nephrectomized rats were used as the rat model of chronic renal failure. Competitive quantitative RT-PCR showed that kisspeptin mRNA levels were decreased in the kidney of 5/6 nephrectomized rats at 56 days compared with sham-operated rats. In contrast, immunoreactive kisspeptin concentrations were increased in the kidney of 5/6 nephrectomized rats at 56 days. On the other hand, kisspeptin receptor mRNA levels were increased in the kidney of 5/6 nephrectomized rats at 14 and 56 days compared with sham-operated rats. Immunocytochemistry showed that kisspeptins and kisspeptin receptor were expressed in renal tubular cells, collecting duct cells, vascular smooth muscle cells in both rats. The intensity of kisspeptin receptor immunostaining was lower in 5/6 nephrectomized rats than in sham-operated rats. Western blot analysis confirmed that kisspeptin receptor protein levels were significantly decreased in the remnant kidney of 5/6 nephrectomized rats (about 23% of sham-operated rats), which is a good contrast to the kisspeptin receptor mRNA expression. The present study has shown that expression of kisspeptins and kisspeptin receptor are altered in the kidney tissues of chronic renal impairment, raising the possibility of their pathophysiological roles in chronic renal failure.
    Peptides 10/2010; 31(10):1920-5. DOI:10.1016/j.peptides.2010.07.001 · 2.62 Impact Factor

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6k Citations
643.70 Total Impact Points


  • 1991-2014
    • Tohoku University
      • • Graduate School of Pharmaceutical Sciences
      • • Department of Molecular Biology and Applied Physiology
      Miyagi, Japan
  • 2004
    • Iwate Medical University
      Morioka, Iwate, Japan
  • 1999
    • Sendai University
      Sendai, Kagoshima, Japan
  • 1997
    • Sendai City Hospital
      Sendai, Kagoshima, Japan
  • 1993
    • Kitasato University
      • Graduate School of Fisheries Sciences
      Edo, Tōkyō, Japan