妊娠高血圧-免疫ネットワークの接点と病態成立機構の解明

• Project/Area Number: 14657037
• Research Category: Grant-in-Aid for Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Pathological medical chemistry
• Research Institution: University of Tsukuba
• Principal Investigator: 深水 昭吉 筑波大学, 大学院・生命環境科学研究科, 教授 (60199172)
• Co-Investigator(Kenkyū-buntansha): 谷本 啓司 筑波大学, 大学院・生命環境科学研究科, 助教授 (90261776) ; 石田 純治 筑波大学, 大学院・生命環境科学研究科, 講師 (30323257)
• Project Period (FY): 2002 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥3,300,000 (Direct Cost: ¥3,300,000); Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000); Fiscal Year 2003: ¥1,000,000 (Direct Cost: ¥1,000,000); Fiscal Year 2002: ¥1,300,000 (Direct Cost: ¥1,300,000)
• Keywords: ヒトレニン / ヒトアンジオテンシノーゲン / 妊娠中毒症 / 妊娠高血圧 / 酸性プロテアーゼ / 胎児発育遅延 / アンジオテンシンII / 臓器障害 / 免疫応答

Research Abstract

近年の急速な少子化の進展は,平均寿命の伸長による高齢者の増加と相まって,我が国の人口構造にひずみを生じさせ,21世紀の国民生活に深刻かつ多大な影響をもたらしています.これは,単に"子供を産むための社会的な環境不備"だけでなく,『出産に伴う様々な危険因子』を回避できないことにも大きく起因しています.
その危険因子の代表格である妊娠中毒症は,高血圧を中心病態として,全身各臓器に多様な病変をきたします.一方,胎児は免疫学的には一種の移植片であるため,母胎相互の免疫制御の破綻が妊娠中毒症を引き起こすとも考えられています.どちらも,重症化によって母子双方に流産を含めた重篤な合併症を伴いますが,その成因については確定されていません.
申請者らは,酸性プロテアーゼであるヒトレニン(hRN)とその基質でありアンジオテンシンIIの前駆体・ヒトアンジオテンシオーゲン(hANG)に関する発生工学的研究を行い,♂hRN導入(-Tg)マウスと交配させた♀hANG-Tgマウスにおいて,妊娠期間特異的に高血圧が誘発されることを世界で初めて発見いたしました.この時に,タンパク尿の排泄,腎臓疾患,胎盤浮腫および求心性心肥大等の臓器障害や痙攣発作を伴う"妊娠中毒症"に類似した症状が見出されました.
そこで本研究は,明確な遺伝的バックグラウンドを持ち,妊娠高血圧が100%発症する申請者らが開発したモデル動物を用い,血圧調節系と免疫系の接点を解明することを目的といたしました.本年度は,妊娠高血圧マウスの胎児発育遅延が,アンジオテンシンII受容体拮抗薬で劇的に改善されることを明らかにしました.今後は,新規7回膜貫通型受容体とアンジオテンシンII受容体の遺伝的拮抗作用を解析していく予定です

Research Products

• [Journal Article] SREBPs suppress IRS-2-mediated insulin signaling in the liver. (2004)
  • Author(s): Ide, T
  • Journal Title: Nat.Cell Biol. 6 Pages: 351-357
• [Journal Article] Endothelin-1 regulates cardiac sympathetic innervation in the rodent heart by controlling nerve growth factor expression. (2004)
  • Author(s): Ieda, M.
  • Journal Title: J.Clin.Invest. 113 Pages: 876-884
• [Journal Article] Bile acids regulate gluconeogenic gene expression via small heterodimer partner-mediated repression of hepatocyte nuclear factor 4 and Foxo1. (2004)
  • Author(s): Yamagata, K.
  • Journal Title: J.Biol.Chem. 279 Pages: 23158-23165
• [Journal Article] Mechanical stress activates angiotensin II type 1 receptor without the involvement of angiotensin II. (2004)
  • Author(s): Zou, Y.
  • Journal Title: Nat.Cell Biol. 6 Pages: 499-506
• [Journal Article] Regulatory roles for APJ, a seven-transmembrane receptor related to angiotensin-type in blood pressure in vivo. (2004)
  • Author(s): Ishida, J.
  • Journal Title: J.Biol.Chem. 279 Pages: 26274-26279
• [Journal Article] Silent information regular 2 potentiates Foxo1-mediated transcription through its deacetylase activity. (2004)
  • Author(s): Daitoku, H.
  • Journal Title: Proc.Natl.Acad.Sci. 101 Pages: 10042-10047
• [Publications] Araya, N.: "Cooperative interaction of EWS with CREB-binding protein selective activates hepatocyte nuclear factor 4-mediated transcription."J.Biol.Chem.. 278. 5427-5432 (2003)
• [Publications] Hirota, K.: "Hepatocyte nuclear factor-4 is a novel downstream target of insulin via FKHR as a signal-regulated transcriptional inhibitor."J.Biol.Chem.. 278. 13056-13060 (2003)
• [Publications] Matsuzaki, H.: "Insulin-induced phosphorylation of FKHR (Foxol) targets to proteasomal degradation."Proc.Natl.Acad.Sci.U.S.A.. 100. 11285-11290 (2003)
• [Publications] Amano, T.: "Synoviolin/Hrd1,an E3 ubiquitin ligase, as a novel pathogenic factor for arthropathy."Genes & Dev.. 17. 2436-2449 (2003)
• [Publications] Shimamoto, Y.: "Inhibitory effect of the small heterodimer partner on hepatocyte nuclear factor-4 mediates bile acid-induced repression of the human angiotensinogen gene."J.Biol.Chem.. 279. 7770-7776 (2004)
• [Publications] Saito, T.: "An essntial role for angiotensin II type la receptor in pregnancy-associated hypertension with intrauterine growth retardation."FASEB J.. 18. 388-390 (2004)
• [Publications] Hatta, M.: "Regulation of alkaline phosphatase promoter activity by forkhead transcription factor FKHR"Int. J. Mol. Med.. 9. 147-152 (2002)
• [Publications] Kawabata, H.: "Possible role of transcriptional coactivator P/CAF and nuclear acetylation in calcium-induced keratinocyte differentiation"J. Biol. Chem.. 277. 8099-8105 (2002)
• [Publications] Saitoh, M.: "The Presence of Both the Amino-and Carboxyl-Terminal Domains in the AR Is Essential for the Completion of a Transcriptionally Active Form with Coactivators and Intranuclear Compartmentalization Common to the Steroid hormone receptors : a three-dimensional imaging study"Mol Endocrinol.. 16. 694-706 (2002)
• [Publications] Takahashi, Y.: "Characterization and idetification of promoter elements in the mouse COX17 gene"Biochim. Biophys. Acta. 1574. 359-364 (2002)
• [Publications] Nakazawa, M.: "TNF α induces acetylation of p53 but attenuates its transcriptional activation in rheumatoid synoviocytes"Int. J. Mol. Med.. 10. 269-275 (2002)
• [Publications] Kang, N.: "Reduced hypertendion-induced end-organ damage in mice lacking cardiac and renal angiotensinogen synthesis"J. Mol. Med.. 80. 359-366 (2002)
• [Publications] Li, Y., kishimoto: "Guanylyl cyclase-A inhibits angiotensin II type 1A receptor-mediated cardiac remodeling an endogeneous protective mechanism in the heart"Circukation. 106. 1722-1728 (2002)
• [Publications] Sano, M.: "Novel method for selection of tRNA-driven ribozymes with enhanced stability in mammalian Cells"J. Biol. Chem.. 12. 341-352 (2002)
• [Publications] Kunori, Y.: "Rodent α-chymases are elastase-like proteases"Eur. J. Biochem.. 269. 5921-5930 (2002)
• [Publications] Araya, N.: "Cooperative interaction of EWS with CREB-binding protein selective activates hepatocyte nuclear factor 4-mediated transcription"J. Biol. Chem.. 278. 5427-5432 (2002)