WT1 and FAK in a pathological mechanism of daibetes nephropathy
| Project/Area Number |
09671149
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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 | University of Tokyo |
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Principal Investigator |
MIMURA Toshihide University of Tokyo, Dept. Medicine, Assit. Professor, 医学部・附属病院, 助手 (30260491)
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| Project Period (FY) |
1997 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 1998: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1997: ¥2,700,000 (Direct Cost: ¥2,700,000)
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| Keywords | FAK / WT1 / Progressive renal failure / Diabetes nephropathy / ACE-I / Glomerular epithelial cells / nested-RT-PCR / focal adhesion kinase / progressive renal damage / glomerularepithelial cell |
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| Research Abstract |
1) The number of glomerular epithelial cells (GECs) was reduced in diabetes nephropathy (DN) kidney as preliminary data shown, however, the expression of p125 Focal adhesion kinase (FAK) and WT1 was almost equal in each GEC to normal kidneys. These data suggest that the expression level of FAK and WT1 in GECs was not significantly reduced in DN.
2) The mutation in genomic WT1 gene was analyzed in 27 end-stage renal disease (ESRD) patients who recently started hemodialysis (HD) treatment. Although there were tendency of increased mutations only in introns in ESRD patients, it was not statistically significant. To analyze mutations in mRNA of WT1, a new technique was developed in my laboratory (submitted). Briefly WT1 cDNA was obtained from patient urine sediments using nested-RT-PCR.Urine WT1 cDNA was detected in approximately 40% DN patients, on the other hand in only 2% diabetes mellitus (DM) patients without proteinuria (submitted). The striking data suggest that GEC damage was develo
… More
ped in DN and the detection of urine WT I could be the novel technique to show renal damage replacing invasive renal biopsy. Utilizing urine WT1 cDNA the extensive mutation search has been in progress in my laboratory.
3) The expression pattern of FAK and WT1 in cultured GEC line was different from that in in vivo-GEC or freshly isolated GEC (in preparation). Long term primary culture of GEC has been established by culturing in the presence of a chemical which is known to reduce WT1 function. Biology of GEC obtained by this method has been studied.
4) Using FAK negative fibroblasts, we showed that Cake, a member of FAK family kinase highly expressed in kidney, could play a similar role of FAK in integrin siganl transduction (Ueki, Mimura et al. FEBS letter, 1998).
5) As we have reported, the expression and tyrosine phosphorylation of FAK increase in glomeruli of OLETF, spontaneous developing DM rat strain, before presence of proteinuria. It could suggest that mechanical stress of GEC due to hyperfiltration induces the FAK expression and tyrosine phosphorylation. It was of interest whether angiotensin converting enzyme inhibitor (ACE-I) could suppress the elevation of FAK in OLETF by reducing intraglomeruli hypertension. Only high dose ACE-I significantly suppressed the increase of expression of FAK in OLETF glomeruli comparing to that of controls (in preparation). These data suggested that hyperfiltration due to diabetes induced expression and tyrosine phosphorylation of FAK which could be at least a part of the pathological mechanism of DN.
The support of this grant has brought to our laboratory and to the medical biology Field several new research results as well as new questions. Less
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Report
(3 results)
Research Products
(15 results)
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[Publications] Ueki, K., Mimura, T., Nakamoto, T., Sasaki, T., Aizawa, S., Hirai, H., Yano, S., Naruse, T., and Nojima, Y.: "Integrin-mediated signal transduction in cells lacking focal adhesion Kinase p125FAK." FEBS Letters. 432. 197-201 (1998)
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[Publications] Hamasaki, K., Mimura, T., Kanda, H., Morino, N., Yazaki, Y., and Nojima, Y.: "Development of systemic lupus erythematosus in a rheumatoid arthritis patient with anti-ribosomal P protein antibody." Lupus. 6. 734-736 (1997)
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[Publications] Kanda, H., Mimura, T., Morino, N., Hamasaki, K., Nakamoto, T., Hirai, H.Morimoto, C., Yazaki, Y., and Nojima, Y.: "Ligation of the T cell antigen receptor induces tyrosine phosphorylation of p105CasL,member of the p130Cas-related docking protein family, and its subsequent binding to the Src homology 2 domain of c-Crk." E.J.Immunol. 27. 2113-2117 (1997)
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[Publications] Mimura, T., Minota, S., Nojima, N., Morino, N., Hamasaki, K., Furuya, H., and Yazaki, Y.: "Constitutive tyrosine phosphorylation of the vav proto-oncogene product in MRL/Mp-lpr/lpr mice." J.Immunol.158. 2977-2983 (1997)
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