| Budget Amount *help |
¥3,800,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥300,000)
Fiscal Year 2007: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2006: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Research Abstract |
We investigated the role of a small G-coupled protein Rho and its downstream target molecule, Rho kinase in the pathogenesis of metabolic syndrome-associated renal insufficiency. From April, 2006, we started the research by using C57BL/6J mice. 6-week-old C57BL/6J mice were randomly divided into three experimental groups; mice fed with low fat diet (group L), mice fed with high-fat diet (group H), and high fat-fed mice treated with Rho kinase inhibitor, Fasudil (group F). Each group was kept for 12 weeks. It has been demonstrated that Fasudil ameliorated urinary protein excretion in high-fat diet-fed mice. We explored its mechanism and found out that Fasudil inhibited the increased expression of MCP-1 and PDGF in the kidney of high fat diet-fed mica From April, 2007, we further examined the role of Rho/Rho kinase pathway in the adipose tissue and adipocytes since these tissues play a central role in the pathogenesis of metabolic syndrome. In the in vitro experiment, we utilized the tis
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sue culture system using 3T3-L1 fibroblasts differentiated into adipocytes. It has been demonstrated that, after mature adipocytes becomes hypertrophic adipocytes, Rho kinase activity was enhanced and the expression of MCP-1 and TNF-a in the adipocytes were increased. Rho kinase inhibitor blocked the activation of Rho kinase concommitently with the downregulation of MCP-1 and TNF-a. In in vivo experiments, we utilized the same diet-induced obesity model. It was demonstrated that Rho-kinase inhibitor, Fasudil inhibited the increase in body weight of high fat diet-fed mice. The weights of adipose tissues were also decreased in group F mice as compared with that in group H mice The sizes of adipocytes were also decreased and the expression levels of adipocytokines were also deceased in group F mice as compared with those in group H mice. These data suggested that Rho/Rho kinase pathway played important roles in the pathogenesis of metabolic syndrome. In the next step, we constructed gene-engineered mice which expressed constitutive active Rho and dominant negative Rho in an adipose-tissue specific manner. In the present we are analyzing the phenotypic changes of these mice and the pathological changes in the adipose tissues and renal tissues. These data would delineate the role of Rho/Rho kinase more specifically than the experiments hitherto performed. Less
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