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

转化生长因子-β1已被证明在维持肾脏组织结构以及肾小球和肾小管功能方面发挥重要作用。转化生长因子-β1通常由正常细胞以生物活性或潜伏期的形式分泌，分子量大。潜伏形式的转化生长因子-β1可能有两种不同的结构：大潜伏的带有LTBP的转化生长因子-β1和不存在转化生长因子-β1的小的潜伏的转化生长因子-β1。本研究采用RT-PCR、原位杂交和免疫组织化学方法，研究了哪些肾细胞产生大或小潜伏的转化生长因子-β1，并试图确定转化生长因子-β1蛋白在正常大鼠和阿霉素诱导的FGS模型大鼠肾脏中的精确定位。在正常的肾脏里。肾小球段和肾小球均有转化生长因子-β1的表达。LTBP mRNA仅在肾小球表达，而在肾小管各段均不表达。提示肾小管上皮细胞分泌少量的潜在的转化生长因子-β1，而肾小球细胞分泌大量的潜伏的转化生长因子-β1。在病变肾脏中，转化生长因子-β生物测定显示，培养的肾脏组织中潜在的转化生长因子-β1的分泌逐渐增加。肾小管上皮细胞也开始分泌大量潜伏的转化生长因子-β1，这与肾小管间质改变的程度密切相关。大量潜伏的转化生长因子-β的增加与细胞外基质(ECM)有关，位于硬化和纤维化组织中。综上所述，肾小管上皮细胞可能是该模型进展过程中大潜伏的转化生长因子-β1的来源，而基质相关的大潜伏转化生长因子-β1可能在硬化性或纤维化病变的细胞外基质代谢中发挥重要作用。

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.