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Functional analysis of mesangial cell syncytium and elucidation of mechanisms involving progressive glomerulosclerosis

系膜细胞合胞体的功能分析和进展性肾小球硬化机制的阐明

基本信息

批准号：
15390266
负责人：
OITE Takashi
金额：
$ 7.42万
依托单位：
Niigata University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390266/
关键词：
renal glomeruli mesangial cells syncytium gap junction glomerulosclerosis experimental animals hemodynamic analysis disturbance of functional regulation 実験動物モデル

项目摘要

1.We have clarified that connexin 43 play an important role of intercellular communication among mesangial cells in co-culture system with endothelial cells, isolated glomeruli, and in vivo. In addition, we found out that co-ordination of renin secretion from granular cells in the paraglomerular apparatus was induced by signal transduction via ATP-purinergic receptor.2.We drew a running hypothesis from our experimental results that loss of physiopathological interaction between endothelial and mesangial cells may cause disturbance of mesagial cell syncytial function, leading to irreversible progression of glomerulosclerosis.3.In high concentration of glucose, the availability of endothelial NOS in cultured glomerular endothelial cells was decreased dramatically, perhaps, by overproduction of superoxide.4.We established a permanent line of cultured human glomerular endothelial cells by transformation with SV40 virus. This cell line is very useful for the standardization of anti-endothelial cell antibody and for establishing culture system of glomerular endothelial cells at large scale.5.We determined the functional epitope of rat Thy-1.1 molecule recognized by monoclonal antibody, named by 1-22-3, one kind of anti-Thy-1.1 antibodies, by the GST-fusion protein method. In vivo binding of 1-22-3 expressed on the surface of mesangial cells results in severe glomerulonephritis.6.Comparing one-kidney and two-kidney groups induced by 1-22-3 injection, we could determine the turning period when the renal disease will divide into reversible or irreversible course.7.Using EGFP-transgenic rats, we could determine the involvement of bone marrow-derived endothelial precursor cells in the regeneration of glomerular endothelial cells. In conclusion, bone marrow-derived endothelial precursor cells recruited play an important role in repairing glomerular injury after severe mesangial cell damage.

1.在体外培养的肾小球系膜细胞与内皮细胞共培养系统、离体肾小球及体内培养的肾小球系膜细胞中，缝隙连接蛋白43在系膜细胞间通讯中发挥重要作用。此外，我们还发现，肾小球旁器颗粒细胞分泌肾素的协调是通过ATP-嘌呤能受体的信号转导引起的。2.我们从我们的实验结果中得出一个假设，即内皮细胞和系膜细胞之间的生理病理相互作用的丧失可能导致系膜细胞合胞体功能的紊乱，3.高浓度葡萄糖可使培养的肾小球内皮细胞NOS活性显著降低，通过SV 40病毒转化培养的人肾小球内皮细胞，建立了人肾小球内皮细胞永久系。该细胞株为抗内皮细胞抗体的标准化和大规模建立肾小球内皮细胞培养体系奠定了基础。5.采用GST-融合蛋白法测定了抗Thy-1.1单克隆抗体1-22-3识别的大鼠Thy-1.1分子的功能表位。1-22-3表达于肾小球系膜细胞表面，在体内结合1 - 22 - 3可导致严重的肾小球肾炎。6.比较1-22-3注射诱导的单肾和双肾组，我们可以确定肾脏疾病将分为可逆或不可逆过程的转折期。我们可以确定骨髓来源的内皮前体细胞参与肾小球内皮细胞的再生。总之，骨髓来源的内皮前体细胞在肾小球系膜细胞严重损伤后的修复中起重要作用。