2002 年度実績報告書

腎疾患の進展におけるインテグリン細胞接着シグナリングの病態生理学的意義

研究課題

研究課題/領域番号	13770616
研究機関	産業医科大学
研究代表者	田村雅仁産業医科大学, 医学部, 助手 (40330980)
キーワード	腎臓病 / 細胞外基質 / 細胞接着 / インテグリン / MCP-1 / FAK
研究概要	種々の腎疾患において、成長因子の発現、糸球体高血圧と細胞外基質の異常産生は共に病態の進展に関与していることが知られているが、これらの相互関係は明らかではない。また、糸球体細胞外基質の増加が細胞接着シグナルを介し、腎炎の進展にどのような影響を与えるのかはほとんど知られていない。我々は成長因子(PDGF)、糸球体高血圧による細胞内シグナル伝達機構とインテグリンを介した細胞接着シグナリングの相互作用を調べ、さらに炎症性ケモカインの一種であるMCP-1の発現に与えるインテグリンの影響も検討した。Fibronectin単独刺激により、時間、濃度依存性にFAKとMEK/ERKのリン酸化が生じた。また圧力負荷やPDGF単独刺激によっても同様に一過性のFAK、MEK/ERKのリン酸化が生じた。さらにfibronectinとPDGF両者の同時刺激により、FAKおよびMEK/ERKの活性化は相乗的に増強した。Dominant-negative FAK (FRNK)の遺伝子導入により、fibronectinとPDGFによるERK活性化への相乗効果が抑制された。Fibronectin濃度依存性に一過性のFAKの活性化が生じると共に、MCP-1 mRNAの発現が増加した。Fibronectinのみならずlamininやtype I、III、IV collagenなどの細胞外基質による刺激でもMCP-1の発現が増加したが、インテグリンを介さない非特異的な細胞接着では増加しなかった。Dominant-negative FAKによりfibronectinによるFAKの活性化とMCP-1 mRNAの発現が抑制された。以上より、腎疾患での細胞外基質と成長因子の過剰発現は、インテグリン/MAP kinaseシグナル伝達経路の活性化を介して相乗的に腎炎の進展に関与している可能性が考えられた。

研究成果
(22件)

すべてその他

すべて文献書誌 (22件)

[文献書誌] Yasuda M: "Stimulation of β1 integrin down-regulates ICAM-1 expression and ICAM-1-dependent adhesion of lung cancer cells through focal adhesion kinase"Cancer Research. 61. 2022-2030 (2001)
[文献書誌] Osajima A: "Clinical significance of natriuretic peptides and cyclic GMP in hemodialysis patients with coronary artery disease"American Journal of Nephrology. 21. 112-119 (2001)
[文献書誌] Suda T: "Pressure induces expression of monocyte chemoattractant protein-1 through activation of MAP kinase in cultured mesangial cells"Kidney International. 60. 1705-1715 (2001)
[文献書誌] Tamura K: "Synergistic interaction of integrin and angiotensin II in activation of extracellular signal-regulated kinase pathways in vascular smooth muscle cells"Journal of Cardiovascular Pharmacology. 38. S59-S62 (2001)
[文献書誌] Iwamoto M: "Adrenomedullin inhibits pressure-induced mesangial MCP-1 expression through activation of protein kinase A"Nephrology Dialysis and Transplantation. 16・6. A15 (2001)
[文献書誌] Ota T: "Tubular expression of monocyte chemoattractant protein-1 (MCP-1) in rat 5/6 nephrectomy model"Nephrology Dialysis and Transplantation. 16・6. A15 (2001)
[文献書誌] Osajima A: "Comparison of mature adrenomedullin levels and natriuretic peptides levels as a useful marker for cardiac function in plasma of hemodialysis patients with coronary artery disease"Journal of American Society of Nephrology. 12. 405A (2001)
[文献書誌] Tamura M: "High glucose inhibits cell spreading, migration, and focal adhesions in peritoneal mesothelial cells"Journal of American Society of Nephrology. 12. 718A (2001)
[文献書誌] Watanabe Y: "Integrin-mediated cell adhesion induces monocyte chemoattractant protein-1 (MCP-1) expression in rat mesangial cells"Journal of American Society of Nephrology. 12. 720A (2001)
[文献書誌] Ota T: "Expression of monocyte chemoattractant protein-1 (MCP-1) in tubulointerstitial lesions of subtotal nephrectomy rats"Journal of American Society of Nephrology. 12. 822A (2001)
[文献書誌] Suda T: "The mature form of adrenomedullin correlates with brain natriuretic peptide in plasma of chronic hemodialysis patients"Clinical Nephrology. 57. 444-451 (2002)
[文献書誌] Aikawa R: "Integrins play a critical role in mechanical stress-induced p38 MAPK activation"Hypertension. 39. 233-238 (2002)
[文献書誌] Ota T: "Expression of monocyte chemoattractant protein-1 in proximal tubular epithelial cells in a rat model of progressive renal failure"Journal of Laboratory and Clinical Medicine. 140. 43-51 (2002)
[文献書誌] Osajima A: "Comparison of plasma levels of mature adrenomedullin and natriuretic peptide as markers of cardiac function in hemodialysis patients with coronary artery disease"Nephron. 92. 832-839 (2002)
[文献書誌] Tamura M: "High glucose inhibits focal adhesion kinase (FAK)-mediated wound healing of peritoneal mesothelial cells"Nephrology Dialysis and Transplantation. 17. S300 (2002)
[文献書誌] Watanabe Y: "Integrin-mediated cell adhesion induces monocyte chemoattractant protein-1 (MCP-1)mRNA expression in cultured rat mesangial cells"Nephrology Dialysis and Transplantation. 17. S71 (2002)
[文献書誌] Osajima A: "Mature adrenomedullin levels are less useful than natriuretic peptides levels as a marker of cardiac function in hemodialysis patients with coronary artery disease"Nephrology Dialysis and Transplantation. 17. S262 (2002)
[文献書誌] Tamura M: "High glucose concentrations inhibits focal adhesion kinase-mediated wound healing of rat peritoneal mesothelial cells"Journal of American Society of Nephrology. 13. 525A (2002)
[文献書誌] Tamura M: "High glucose levels inhibit focal adhesion kinase-mediated wound healing of rat peritoneal mesothelial cells. Kidney Int.63:722-731"Kidney International. 63. 722-731 (2003)
[文献書誌] Tamura K: "Urotensin II-induced activation of extracellular signal-regulated kinase in cultured vascular smooth muscle cells : Involvement of cell adhesion-mediated integrin signaling"Life Science. 72. 1049-1060 (2003)
[文献書誌] Nakayamada S: "β1 integrin-mediated signaling induces ICAM-1 and Fas and Fas-mediated apoptosis of rheumatoid synovial cells"Arthritis and Rheumatology. (In press).
[文献書誌] Watanabe Y: "Integrins induce expression of monocyte chemoattractant protein-1 via focal adhesion kinase in mesangial cells"Kidney International. (In press).

2002 年度 実績報告書

腎疾患の進展におけるインテグリン細胞接着シグナリングの病態生理学的意義

研究代表者

田村 雅仁 産業医科大学, 医学部, 助手 (40330980)

研究成果

[文献書誌] Yasuda M: "Stimulation of β1 integrin down-regulates ICAM-1 expression and ICAM-1-dependent adhesion of lung cancer cells through focal adhesion kinase"Cancer Research. 61. 2022-2030 (2001)

[文献書誌] Osajima A: "Clinical significance of natriuretic peptides and cyclic GMP in hemodialysis patients with coronary artery disease"American Journal of Nephrology. 21. 112-119 (2001)

[文献書誌] Suda T: "Pressure induces expression of monocyte chemoattractant protein-1 through activation of MAP kinase in cultured mesangial cells"Kidney International. 60. 1705-1715 (2001)

[文献書誌] Tamura K: "Synergistic interaction of integrin and angiotensin II in activation of extracellular signal-regulated kinase pathways in vascular smooth muscle cells"Journal of Cardiovascular Pharmacology. 38. S59-S62 (2001)

[文献書誌] Iwamoto M: "Adrenomedullin inhibits pressure-induced mesangial MCP-1 expression through activation of protein kinase A"Nephrology Dialysis and Transplantation. 16・6. A15 (2001)

[文献書誌] Ota T: "Tubular expression of monocyte chemoattractant protein-1 (MCP-1) in rat 5/6 nephrectomy model"Nephrology Dialysis and Transplantation. 16・6. A15 (2001)

[文献書誌] Osajima A: "Comparison of mature adrenomedullin levels and natriuretic peptides levels as a useful marker for cardiac function in plasma of hemodialysis patients with coronary artery disease"Journal of American Society of Nephrology. 12. 405A (2001)

[文献書誌] Tamura M: "High glucose inhibits cell spreading, migration, and focal adhesions in peritoneal mesothelial cells"Journal of American Society of Nephrology. 12. 718A (2001)

[文献書誌] Watanabe Y: "Integrin-mediated cell adhesion induces monocyte chemoattractant protein-1 (MCP-1) expression in rat mesangial cells"Journal of American Society of Nephrology. 12. 720A (2001)

[文献書誌] Ota T: "Expression of monocyte chemoattractant protein-1 (MCP-1) in tubulointerstitial lesions of subtotal nephrectomy rats"Journal of American Society of Nephrology. 12. 822A (2001)

[文献書誌] Suda T: "The mature form of adrenomedullin correlates with brain natriuretic peptide in plasma of chronic hemodialysis patients"Clinical Nephrology. 57. 444-451 (2002)

[文献書誌] Aikawa R: "Integrins play a critical role in mechanical stress-induced p38 MAPK activation"Hypertension. 39. 233-238 (2002)

[文献書誌] Ota T: "Expression of monocyte chemoattractant protein-1 in proximal tubular epithelial cells in a rat model of progressive renal failure"Journal of Laboratory and Clinical Medicine. 140. 43-51 (2002)

[文献書誌] Osajima A: "Comparison of plasma levels of mature adrenomedullin and natriuretic peptide as markers of cardiac function in hemodialysis patients with coronary artery disease"Nephron. 92. 832-839 (2002)

[文献書誌] Tamura M: "High glucose inhibits focal adhesion kinase (FAK)-mediated wound healing of peritoneal mesothelial cells"Nephrology Dialysis and Transplantation. 17. S300 (2002)

[文献書誌] Watanabe Y: "Integrin-mediated cell adhesion induces monocyte chemoattractant protein-1 (MCP-1)mRNA expression in cultured rat mesangial cells"Nephrology Dialysis and Transplantation. 17. S71 (2002)

[文献書誌] Osajima A: "Mature adrenomedullin levels are less useful than natriuretic peptides levels as a marker of cardiac function in hemodialysis patients with coronary artery disease"Nephrology Dialysis and Transplantation. 17. S262 (2002)

[文献書誌] Tamura M: "High glucose concentrations inhibits focal adhesion kinase-mediated wound healing of rat peritoneal mesothelial cells"Journal of American Society of Nephrology. 13. 525A (2002)

[文献書誌] Tamura M: "High glucose levels inhibit focal adhesion kinase-mediated wound healing of rat peritoneal mesothelial cells. Kidney Int.63:722-731"Kidney International. 63. 722-731 (2003)

[文献書誌] Tamura K: "Urotensin II-induced activation of extracellular signal-regulated kinase in cultured vascular smooth muscle cells : Involvement of cell adhesion-mediated integrin signaling"Life Science. 72. 1049-1060 (2003)

[文献書誌] Nakayamada S: "β1 integrin-mediated signaling induces ICAM-1 and Fas and Fas-mediated apoptosis of rheumatoid synovial cells"Arthritis and Rheumatology. (In press).

[文献書誌] Watanabe Y: "Integrins induce expression of monocyte chemoattractant protein-1 via focal adhesion kinase in mesangial cells"Kidney International. (In press).

2002 年度実績報告書

田村雅仁産業医科大学, 医学部, 助手 (40330980)