| Project/Area Number |
17590853
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Kidney internal medicine
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| Research Institution | Research Institute for Production Development |
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Principal Investigator |
ABE Hideharu Research Institute for Production Development, Molecular and Renal Pathology Laboratory, Research Scientist, 腎病態解析研究室, 研究員 (60399342)
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| Co-Investigator(Kenkyū-buntansha) |
ARAI Hidenori Kyoto University, Department of Geriatric Medicine, Lecturer, 大学院医学研究科, 講師 (60232021)
MIZUNO Akira The University of Tokushima, Department of Laboratory Medicine, School of Medicine, Assistant Professor, 医学部・歯学部附属病院, 助手 (80219641)
TSUKAGUCHI Hiroyasu The University School of Tokushima Graduate, Department of Clinical Biology and Medicine, Institute of Health Biosciences, Assistant Professor, 大学院ヘルスバイオサイエンス研究部, 助手 (60335792)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2005: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Keywords | diabetic nephropathy / Smad1 / α-smooth muscle actin / BMP4 / angiotensin II / type IV collagen / glomerulosclerosis / Src / smad1 / Id2 / ALK |
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| Research Abstract |
We studied the signaling mechanisms of Smad1-related genes, which play important roles in the process of diabetic nephropathy. We demonstrated that Smad1 is a key transcriptional factor by regulating the expression of type IV collagen (Co14) and α-smooth muscle actin, and plays a critical role for the progression of mesangial matrix expansion in diabetic nephropathy in vivo. Our study also indicates that the amount of urinary Smad1 excretion would be a better diagnostic marker than albuminuria to assess mesangial matrix expansion in diabetic nephropathy. We also demonstrated that AGEs induced BMP4, Smad1, and Col4 mRNA and protein expressions in mesangial cells. TGF-β neutralizing antibody or Noggin (a BMP antagonist) inhibited these inductions. Moreover knockdown of ALK3/6 by using siRNA transfection against each gene blocked the induction. Furthermore, Smad1 and BMP4 were highly expressed in sclerotic regions of diabetic nephropathy mice. These results suggest that the modulation of both TGF-β/Smad1 and BMP4/Smad1 signaling is deeply responsible for initiation and progression of diabetic nephropathy and that blocking of Smad1 signaling pathway may be beneficial for diabetic complications.
Angiotensin II (Ang II) is known to play a pivotal role in the development of diabetic nephropathy. However, the precise mechanism of Ang II-mediated effects on diabetic nephropathy is still unknown. We first showed that Ang II increased expression of Smad1, phospho-Smad1, and phospho-Src in vitro and in vivo, and these inductions were inhibited by olmesartan, PP2, a Src tyrosine kinase inhibitor, and overexpression of dominant negative Src. Moreover, addition of siRNA against Src significantly reduced the phosphorylation of Smad1 and synthesis of Col4. These results indicate that Ang II can regulate the development of mesangial matrix expansion in the early phase of diabetic nephropathy through Src and Smad1.
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