Krag S, Osterby R, Chai Q, Nielsen C B, Hermans C, Wogensen L
The Research Laboratory for Biochemical Pathology, The Institute of Experimental Clinical Research, Aarhus Kommunehospital, Denmark.
Lab Invest. 2000 Dec;80(12):1855-68. doi: 10.1038/labinvest.3780196.
Transforming growth factor-beta1 (TGF-beta1) may play a major role in the pathogenesis of glomerulopathy and end-stage renal disease (ESRD). The aim of this study was to explore the functional consequences of localized overproduction of TGF-beta1 in relation to glomerular ultrastructure and the composition of the extracellular matrix (ECM) in the inner medulla. We used a transgenic mouse with overexpression of TGF-beta1 targeted to the juxtaglomerular apparatus (JGA) by the Ren-1c promoter. The kidney function was evaluated using urine production and metabolite excretion over a 24-hour period, glomerular filtration rate (GFR), and concentrating ability. The glomerular structure was analyzed in terms of volume, ie, the volume of the mesangium per glomerulus (Vv[mes/glom]) and the volume of the matrix per glomerulus (Vv[matrix/glom]), ECM per glomerulus, the area of the filtration surface, and the thickness of the peripheral basement membrane (PBM). Immunohistochemistry or in situ hybridization was used to examine the expression of aquaporin 2 (AQP2), plasminogen activator inhibitor-1 (PAI-1), and the composition of the ECM in the inner medulla. The mice exhibited polyuria, reduced concentrating ability, decreased GFR, and albuminuria paralleled by increased glomerular volume, with increased volume of ECM, decreased filtration surface, and thickening of the PBM being detectable between 1 and 2 months of age. The deposition of glomerular ECM was accompanied by increased levels of PAI-1. As estimated by excretion of Clara cell protein-1 (CC16) and lysozyme, tubular damage occurred only in older mice. Collagen Type I was deposited in the inner medulla in the presence of normal AQP2-expression in the collecting ducts. This study reached the following conclusions: (a) TGF-beta1 reduces the GFR and the glomerular filtration surface, (b) TGF-beta1 induces albuminuria in association with widening of the PBM, (c) expansion of the mesangial volume seems to precede the widening of the PBM, (d) TGF-beta1-induced accumulation of glomerular ECM is partly explained by increased PAI-1 expression, (e) Decreased concentrating ability and polyuria caused by accumulation of ECM in the inner medulla may be an early marker of glomerular diseases associated with increased expression of TGF-beta1 in man.
转化生长因子-β1（TGF-β1）可能在肾小球病和终末期肾病（ESRD）的发病机制中起主要作用。本研究的目的是探讨局部过量产生的TGF-β1与肾小球超微结构以及髓质内层细胞外基质（ECM）组成的功能关系。我们使用了一种转基因小鼠，其通过Ren-1c启动子使TGF-β1在肾小球旁器（JGA）中过表达。通过24小时尿量和代谢产物排泄、肾小球滤过率（GFR）以及浓缩能力来评估肾功能。从体积方面分析肾小球结构，即每个肾小球系膜的体积（Vv[系膜/肾小球]）、每个肾小球基质的体积（Vv[基质/肾小球]）、每个肾小球的ECM、滤过表面面积以及外周基底膜（PBM）的厚度。采用免疫组织化学或原位杂交技术检测水通道蛋白2（AQP2）、纤溶酶原激活物抑制剂-1（PAI-1）的表达以及髓质内层ECM的组成。这些小鼠表现出多尿、浓缩能力降低、GFR下降和蛋白尿，同时肾小球体积增大，在1至2月龄时可检测到ECM体积增加、滤过表面减小以及PBM增厚。肾小球ECM的沉积伴随着PAI-1水平的升高。根据克拉拉细胞蛋白-1（CC16）和溶菌酶的排泄估计，肾小管损伤仅发生在老年小鼠中。在集合管中AQP-2表达正常的情况下，I型胶原沉积在髓质内层。本研究得出以下结论：（a）TGF-β1降低GFR和肾小球滤过表面；（b）TGF-β1诱导蛋白尿并伴有PBM增宽；（c）系膜体积扩大似乎先于PBM增宽；（d）TGF-β1诱导的肾小球ECM积聚部分是由于PAI-1表达增加所致；（e）髓质内层ECM积聚导致的浓缩能力降低和多尿可能是人类中与TGF-β1表达增加相关的肾小球疾病的早期标志物。
