Lee L K, Meyer T W, Pollock A S, Lovett D H
Department of Medicine, San Francisco Veterans Administration Medical Center/University of California 94121, USA.
J Clin Invest. 1995 Aug;96(2):953-64. doi: 10.1172/JCI118143.
The development of progressive glomerulosclerosis in the renal ablation model has been ascribed to a number of humoral and hemodynamic events, including the peptide growth factor, transforming growth factor-beta 1 (TGF-beta 1). An important role has also been attributed to angiotensin II (AII), which, in addition to its hemodynamic effects, can stimulate transcription of TGF-beta 1. We postulated that increased glomerular production of AII, resulting from enhanced intrinsic angiotensinogen expression, stimulates local TGF-beta 1 synthesis, activating glomerular matrix protein synthesis, and leads to sclerosis. Using in situ reverse transcription, the glomerular cell sites of alpha-1 (IV) collagen, fibronectin, laminin B1, angiotensinogen, and TGF-beta 1 mRNA synthesis were determined at sequential periods following renal ablation. The early hypertrophic phase was associated with global, but transient, increases in the mRNA for alpha-1 (IV) collagen. No changes were noted for fibronectin, TGF-beta 1, and angiotensinogen mRNAs. At 24 d after ablation, at which time sclerosis is not evident, endothelial cells, particularly in the dilated capillaries at the vascular pole, expressed angiotensinogen and TGF-beta 1 mRNAs, as well as fibronectin and laminin B1 RNA transcripts. By 74 d after ablation angiotensinogen and TGF-beta 1 mRNAs were widely distributed among endothelial and mesangial cells, and were particularly prominent in regions of evolving sclerosis. These same regions were also notable for enhanced expression of matrix protein mRNAs, particularly fibronectin. All receptor blockade inhibited angiotensinogen, TGF-beta 1, fibronectin, and laminin B1 mRNA expression by the endothelium. We conclude that, as a result of hemodynamic changes, injured or activated endothelium synthesizes angiotensinogen, triggering a cascade of TGF-beta 1 and matrix protein gene expression with resultant development of the segmental glomerular sclerotic lesion.
肾切除模型中进行性肾小球硬化的发展归因于多种体液和血流动力学事件，包括肽生长因子转化生长因子-β1（TGF-β1）。血管紧张素II（AII）也被认为起着重要作用，它除了具有血流动力学效应外，还能刺激TGF-β1的转录。我们推测，由于内源性血管紧张素原表达增强导致肾小球AII生成增加，刺激局部TGF-β1合成，激活肾小球基质蛋白合成，进而导致硬化。采用原位逆转录法，在肾切除后的连续时间段内，确定α-1（IV）胶原、纤连蛋白、层粘连蛋白B1、血管紧张素原和TGF-β1 mRNA合成的肾小球细胞位点。早期肥厚阶段与α-1（IV）胶原mRNA的整体但短暂增加有关。纤连蛋白、TGF-β1和血管紧张素原mRNA未见变化。切除后24天，此时硬化不明显，内皮细胞，特别是血管极扩张毛细血管中的内皮细胞，表达血管紧张素原和TGF-β1 mRNA，以及纤连蛋白和层粘连蛋白B1 RNA转录本。切除后74天，血管紧张素原和TGF-β1 mRNA广泛分布在内皮细胞和系膜细胞中，在正在形成硬化的区域尤为突出。这些相同区域的基质蛋白mRNA，特别是纤连蛋白的表达也增强。所有受体阻断均抑制内皮细胞的血管紧张素原、TGF-β1、纤连蛋白和层粘连蛋白B1 mRNA表达。我们得出结论，由于血流动力学变化，受损或活化的内皮细胞合成血管紧张素原，引发TGF-β1和基质蛋白基因表达的级联反应，导致节段性肾小球硬化病变的发展。
