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THE PERSISTENT ACTIVATION MECHANISM OF TGF-b IN PROGRESSIVE GLOMERULAR DISEASES

进展性肾小球疾病中TGF-b的持续激活机制

基本信息

批准号：
06671143
负责人：
OKUDA Seiya
金额：
$ 1.41万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06671143/
关键词：
Growth factor TGF-b TGF-b binding protein Glomerulosclerosis Interstitial fibrosis matrix TGF-b localization TGF-b acctivation LTBP PCR 尿細管細胞

项目摘要

TGF-beta1 has been shown to play an important role in maintaining the renal histological structure as well as the glomerular and tubular functions. TGF-beta1 is usually secreted by normal cells in a biologically inactive or latent form with a high molecular weight. The latent form of TGF-beta1 may have two different structures of large latent TGF-beta1 with LTBP and small latent TGF-beta1 without LTBP.LTBP plays a central role in the assembly, secretion, activation and localization of TGF-beta1. In the present study, we investigated which renal cells produce large or small latent TGF-beta1 and also tried to determine the precise localization of TGF-beta1 protein in the kidney of normal rats or adriamycin-induced FGS model rats, using RT-PCR,in situ hybridization and immunohistochemistory. In the normal kidney. TGF-beta1 mRNA was detected in all nephron segments and glomeruli. On the other hand, LTBP mRNA was present only in the glomeruli, while it was absent in every segment of the renal tubules. This finding suggested that the tubular cells secrete small latent TGF-beta1, while glomerular cells secrete large latent TGF-beta1. In the diseased kidney, a TGF-beta bioassay revealed a progressive increase in latent TGF-beta1 secretion from cultured renal tissues. The tubular cells also began to secrete large latent TGF-beta1, which closely paralleled the degree of the tubulointerstitial changes. The increased amount of large latent TGF-beta was localized in the sclerotic and fibrotic tissue in association with the extracellular matrix (ECM). In conclusion, the tubular cells might thus turn out to be a source of large latent TGF-beta1 in progressive process of this model, while matrix-associated large latent TGF-beta1 may play an important role in the ECM metabolism of either sclerotic or fibrotic lesions.

tgf - β 1已被证明在维持肾脏组织结构以及肾小球和小管功能方面发挥重要作用。tgf - β 1通常由正常细胞以高分子量的生物无活性或潜伏形式分泌。TGF-beta1的潜伏形式可能有两种不同的结构，即有LTBP的大潜伏TGF-beta1和无LTBP的小潜伏TGF-beta1。LTBP在tgf - β 1的组装、分泌、激活和定位中起核心作用。本研究通过RT-PCR、原位杂交和免疫组织化学等方法，研究了哪些肾细胞产生了大或小的潜伏TGF-beta1，并试图确定TGF-beta1蛋白在正常大鼠或阿霉素诱导的FGS模型大鼠肾脏中的精确定位。在正常的肾脏中。各肾单位节段及肾小球均检测到tgf - β 1 mRNA。另一方面，LTBP mRNA仅在肾小球中存在，而在肾小管的各个节段均不存在。这一发现提示小管细胞分泌少量潜伏的TGF-beta1，而肾小球细胞分泌大量潜伏的TGF-beta1。在病变肾脏中，tgf - β生物测定显示培养肾组织中潜伏的tgf - β分泌逐渐增加。小管细胞也开始分泌大量的潜伏tgf - β 1，这与小管间质改变的程度密切相关。大量潜在tgf - β的增加与细胞外基质（ECM）有关，并局限于硬化和纤维化组织。综上所述，在该模型的进展过程中，小管细胞可能是大潜伏TGF-beta1的来源，而基质相关的大潜伏TGF-beta1可能在硬化或纤维化病变的ECM代谢中发挥重要作用。