2000 Fiscal Year Annual Research Report

アドレノメデュリンの生理的・臨床的意義に関する発生学的・分子医学的研究

Research Project

Project/Area Number	10218204
Research Institution	Kyoto University
Principal Investigator	中尾一和京都大学, 医学研究科, 教授 (00172263)
Co-Investigator(Kenkyū-buntansha)	斎藤能彦京都大学, 医学研究科, 助教授 (30250260) 向山政志京都大学, 医学研究科, 助手 (40270558) 伊藤裕京都大学, 医学研究科, 講師 (40252457) 小川佳宏京都大学, 医学研究科, 助手 (70291424)
Keywords	アドレノメデュリン / アドレノメデュリン受容体 / RAMP / 血管発生 / 血管障害 / 内皮細胞 / 酸化ストレス / 腎障害
Research Abstract	1.血管発生・分化におけるAMの意義の検討 AMの血管発生・分化における意義を検討するため、まずFACSを用いたcell sortingにより同定した新しい血管前駆細胞(vascular progenitor cell)を用いてin vitro、in vivoでの血管発生モデルを開発した(Nature 2000)。即ち、マウスES細胞より中胚葉マーカーであるFlk1+の細胞をFACSにてソーティングし、IV型コラーゲン上で再培養することで内皮細胞の分化誘導に成功、さらにPDGF等の添加再培養により血管平滑筋細胞の誘導にも成功した。またこれらの前駆細胞のゲル内3次元培養により、内皮による管腔構造と血管周皮細胞を有する完全な血管構築の構成にも成功した。この血管発生モデルを用いて、AM受容体コンポーネントの発現を解析し、初期段階からRAMP2の発現を認め、AMが血管発生に意義を有する可能性が示唆された。 2.血管障害・リモデリングにおけるAMの意義の検討高血圧や動脈硬化の病態に内皮障害の重要性が注目されている。我々は培養系を用いて、shear stressに加え酸化ストレスが内皮からのAMの産生・分泌を亢進させることを見出した(J Hypertens2000)。さらにAM特異的モノクローナル抗体による中和実験より、内皮からのAMがautocrine調節因子として強力な増殖抑制とともにエンドセリン分泌抑制作用を有することを示し、AMが血管障害に抑制的に働く可能性が示唆された。 3.腎臓におけるAMおよびその受容体の病態生理的意義の検討 AMおよび受容体は腎糸球体や尿細管に発現し、autocrine/paracrine調節因子として働く可能性が想定される。我々はAM受容体のコンポーネントであるCRLRおよびRAMPファミリーのうち、ラットRAMP1,2,3のクローニングを行い、ヒトと高い相同性(65-85%)を有することを明らかにした(BBRC2000)。またラット腎臓における発現を検討し、基礎時ではRAMP3の発現が主であるが、間質線維化水腎症モデルではRAMP1,2の著明な発現亢進を来すことを見出し、腎障害時に受容体レベルで著しい発現変化が起こることを示した(BBRC)。またAMは培養メサンギウム細胞や間質線維芽細胞の増殖を抑制し、病態時に抑制的に働く可能性が示唆された。

Research Products
(18 results)

All Other

All Publications (18 results)

[Publications] Jun Yamashita: "Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors."Nature. 408(6808). 92-96 (2000)
[Publications] Tae-Hwa Chun: "Oxidative stress augments secretion of endothelium-derived relaxing peptides, C-type natriuretic peptide and adrenomedullin."Journal of Hypertension. 18(5). 575-580 (2000)
[Publications] Tetsuya Nagae: "Rat receptor-activity-modifying proteins (RAMPs) for adrenomedullin/CGRP receptor : Cloning and upregulation in obstructive nephropathy."Biochemical and Biophysical Research Communications. 270(1). 89-93 (2000)
[Publications] Naohisa Tamura: "Cardiac fibrosis in mice lacking brain natriuretic peptide."Proceedings of National Academy of Sciences in USA. 97(8). 4239-4244 (2000)
[Publications] Naoki Sawada: "Inhibition of rho-associated kinase results in suppression of neointimal formation of balloon-injured arteries."Circulation. 101(17). 2030-2033 (2000)
[Publications] Masato Kasahara: "Ameliorated glomerular injury in mice overexpressing brain natriuretic peptide with renal ablation."Journal of American Society of Nephrology. 11(9). 1691-1701 (2000)
[Publications] Hideki Chusho: "Genetic models reveal that brain natriuretic peptide can signal through different tissue-specific receptor-mediated pathways."Endocrinology. 141(10). 3807-3813 (2000)
[Publications] Yoshihiro Miyamoto: "Replication protein A1 reduces transcription of the end othelial nitric oxidesynthase gene containing a -786T-> C mutation associated with coronary spastic angina."Human Molecular Genetics. 9(18). 2629-2637 (2000)
[Publications] Koichiro Kuwahara: "Cardiotrophin-1 phosphorylates akt and BAD, and prolongs cell survival via a PI3K-dependent pathway in cardiac myocytes."Journal of Molecular and Cellular Cardiology. 32(8). 1385-1394 (2000)
[Publications] Ichiro Hamanaka: "Effects of cardiotrophin-1 on hemodynamics and endocrine function of the heart."American Journal of Physiology. 279(1). H388-H396 (2000)
[Publications] Naoki Sawada: "cGMP-dependent protein kinase phosphorylates and inactivates RhoA."Biochemical and Biophysical Research Communications. 280(3). 798-805 (2001)
[Publications] Koichiro Kuwahara: "The neuron-restrictive silencer element/neuron-restrictive silencer factor system regulates basal and endothelin 1-inducible atrial natriuretic peptide gene expression in ventricular myocytes."Molecular and Cellular Biology. 21(6). 2085-2097 (2001)
[Publications] Hideki Chusho: "Dwarfism and early death in mice lacking C-type natriuretic peptide."Proceedings of National Academy of Sciences in USA. (発表予定). (2001)
[Publications] Yasutomo Fukunaga: "Thiazolidinediones, peroxisome proliferator-activated receptor γ agonists regulate endothelial cell growth and secretion of vasoactive peptides."Atherosclerosis. (発表予定). (2001)
[Publications] Kentaro Doi: "C-type natriuretic peptide induces re-differentiation of vascular smooth muscle cells with accelerated re-endothelialization."Arteriosclerosis, Thrombosis and Vascular Biology. (発表予定). (2001)
[Publications] Ichiro Hamanaka: "Induction of JAB/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3 is involved in gp 130 resistance in cardiovascular system in rats treated with cardiotrophin-1(CT-1)in vivo."Circulation Research. (発表予定). (2001)
[Publications] Takayoshi Suganami: "Altered growth response to prostaglandin E2 and its receptor signaling in mesangial cells from stroke-prone spontaneously hypertensive rats."Journal of Hypertension. (発表予定). (2001)
[Publications] Masayo Nakagawa: "Monoclonal antibody against brain natriuretic peptide (BNP) and characterization of BNP-transgenic mice."Journal of Hypertension. (発表予定). (2001)

2000 Fiscal Year Annual Research Report

アドレノメデュリンの生理的・臨床的意義に関する発生学的・分子医学的研究

Principal Investigator

中尾 一和 京都大学, 医学研究科, 教授 (00172263)

Research Products

[Publications] Jun Yamashita: "Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors."Nature. 408(6808). 92-96 (2000)

[Publications] Tae-Hwa Chun: "Oxidative stress augments secretion of endothelium-derived relaxing peptides, C-type natriuretic peptide and adrenomedullin."Journal of Hypertension. 18(5). 575-580 (2000)

[Publications] Tetsuya Nagae: "Rat receptor-activity-modifying proteins (RAMPs) for adrenomedullin/CGRP receptor : Cloning and upregulation in obstructive nephropathy."Biochemical and Biophysical Research Communications. 270(1). 89-93 (2000)

[Publications] Naohisa Tamura: "Cardiac fibrosis in mice lacking brain natriuretic peptide."Proceedings of National Academy of Sciences in USA. 97(8). 4239-4244 (2000)

[Publications] Naoki Sawada: "Inhibition of rho-associated kinase results in suppression of neointimal formation of balloon-injured arteries."Circulation. 101(17). 2030-2033 (2000)

[Publications] Masato Kasahara: "Ameliorated glomerular injury in mice overexpressing brain natriuretic peptide with renal ablation."Journal of American Society of Nephrology. 11(9). 1691-1701 (2000)

[Publications] Hideki Chusho: "Genetic models reveal that brain natriuretic peptide can signal through different tissue-specific receptor-mediated pathways."Endocrinology. 141(10). 3807-3813 (2000)

[Publications] Yoshihiro Miyamoto: "Replication protein A1 reduces transcription of the end othelial nitric oxidesynthase gene containing a -786T-> C mutation associated with coronary spastic angina."Human Molecular Genetics. 9(18). 2629-2637 (2000)

[Publications] Koichiro Kuwahara: "Cardiotrophin-1 phosphorylates akt and BAD, and prolongs cell survival via a PI3K-dependent pathway in cardiac myocytes."Journal of Molecular and Cellular Cardiology. 32(8). 1385-1394 (2000)

[Publications] Ichiro Hamanaka: "Effects of cardiotrophin-1 on hemodynamics and endocrine function of the heart."American Journal of Physiology. 279(1). H388-H396 (2000)

[Publications] Naoki Sawada: "cGMP-dependent protein kinase phosphorylates and inactivates RhoA."Biochemical and Biophysical Research Communications. 280(3). 798-805 (2001)

[Publications] Koichiro Kuwahara: "The neuron-restrictive silencer element/neuron-restrictive silencer factor system regulates basal and endothelin 1-inducible atrial natriuretic peptide gene expression in ventricular myocytes."Molecular and Cellular Biology. 21(6). 2085-2097 (2001)

[Publications] Hideki Chusho: "Dwarfism and early death in mice lacking C-type natriuretic peptide."Proceedings of National Academy of Sciences in USA. (発表予定). (2001)

[Publications] Yasutomo Fukunaga: "Thiazolidinediones, peroxisome proliferator-activated receptor γ agonists regulate endothelial cell growth and secretion of vasoactive peptides."Atherosclerosis. (発表予定). (2001)

[Publications] Kentaro Doi: "C-type natriuretic peptide induces re-differentiation of vascular smooth muscle cells with accelerated re-endothelialization."Arteriosclerosis, Thrombosis and Vascular Biology. (発表予定). (2001)

[Publications] Ichiro Hamanaka: "Induction of JAB/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3 is involved in gp 130 resistance in cardiovascular system in rats treated with cardiotrophin-1(CT-1)in vivo."Circulation Research. (発表予定). (2001)

[Publications] Takayoshi Suganami: "Altered growth response to prostaglandin E2 and its receptor signaling in mesangial cells from stroke-prone spontaneously hypertensive rats."Journal of Hypertension. (発表予定). (2001)

[Publications] Masayo Nakagawa: "Monoclonal antibody against brain natriuretic peptide (BNP) and characterization of BNP-transgenic mice."Journal of Hypertension. (発表予定). (2001)

中尾一和京都大学, 医学研究科, 教授 (00172263)