Gilbert R E, Wilkinson-Berka J L, Johnson D W, Cox A, Soulis T, Wu L L, Kelly D J, Jerums G, Pollock C A, Cooper M E
University of Melbourne Department of Medicine, Victoria, Australia.
Kidney Int. 1998 Oct;54(4):1052-62. doi: 10.1046/j.1523-1755.1998.00081.x.
Transforming growth factor-beta (TGF-beta) has been implicated in the pathogenesis of a number of kidney diseases characterized by glomerulosclerosis and tubulointerstitial fibrosis. TGF-beta is secreted in a latent form requiring extracellular modification to become biologically active. TGF-beta inducible gene-h3 (beta ig-h3) is a recently identified TGF-beta-induced gene product. The present study sought to examine beta ig-h3 expression in normal and diabetic rats.
Beta ig-h3, TGF-beta1 and alpha1 (IV) collagen gene expression were assessed by Northern blot analysis and in situ hybridization in 20 Sprague Dawley rats, randomly assigned to receive streptozotocin (diabetic, N = 11) or citrate buffer alone (control, N = 9) and sacrificed eight months later. The effect of exogenous TGF-beta1 on beta ig-h3 expression was also assessed in cultured proximal tubular cells.
In situ hybridization localized beta ig-h3 gene expression to the juxtaglomerular apparatus and the pars recta (S3 segment) of proximal tubules in both control and diabetic animals. Kidney TGF-beta 1, beta ig-h3 and alpha1 (IV) collagen mRNA from diabetic rats were increased two- to threefold compared with controls (P < 0.01). There was a significant correlation between TGF-beta1 and beta ig-h3 gene expression in kidneys from diabetic rats (r = 0.73, P = 0.01). In addition, beta ig-h3 mRNA increased in response to exogenous TGF-beta1 in a dose-dependent fashion in cultured proximal tubular cells.
These findings support the hypothesis that biologically active TGF-beta plays a pathogenetic role in diabetic kidney disease and suggest that beta ig-h3 may be a useful index of TGF-beta1 bioactivity in the kidney.
转化生长因子-β（TGF-β）与多种以肾小球硬化和肾小管间质纤维化为特征的肾脏疾病的发病机制有关。TGF-β以潜伏形式分泌，需要细胞外修饰才能具有生物活性。TGF-β诱导基因-h3（βig-h3）是最近鉴定出的一种TGF-β诱导基因产物。本研究旨在检测正常大鼠和糖尿病大鼠中βig-h3的表达。
采用Northern印迹分析和原位杂交技术，对20只Sprague Dawley大鼠进行βig-h3、TGF-β1和α1（IV）胶原基因表达评估。这些大鼠被随机分为两组，一组接受链脲佐菌素（糖尿病组，N = 11），另一组仅接受柠檬酸盐缓冲液（对照组，N = 9），8个月后处死。同时，还评估了外源性TGF-β1对培养的近端肾小管细胞中βig-h3表达的影响。
原位杂交显示，在对照组和糖尿病组动物中，βig-h3基因表达定位于肾小球旁器和近端肾小管的直部（S3段）。与对照组相比，糖尿病大鼠肾脏中的TGF-β1、βig-h3和α1（IV）胶原mRNA增加了2至3倍（P < 0.01）。糖尿病大鼠肾脏中TGF-β1和βig-h3基因表达之间存在显著相关性（r = 0.73，P = 0.01）。此外，在培养的近端肾小管细胞中，外源性TGF-β1以剂量依赖性方式增加了βig-h3 mRNA的表达。
这些发现支持了生物活性TGF-β在糖尿病肾病发病机制中起致病作用的假说，并表明βig-h3可能是肾脏中TGF-β1生物活性的有用指标。
