Ruiz-Ortega M, Egido J
Renal Unit, Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain.
Kidney Int. 1997 Dec;52(6):1497-510. doi: 10.1038/ki.1997.480.
The renin-angiotensin system seems to play an important role in the pathogenesis of renal interstitial fibrosis. However, the potential direct effects of angiotensin II (Ang II) on cultured renal fibroblasts have been little studied. We have observed that rat renal interstitial fibroblasts (NRK 49F cell line) possess AT1 receptors coupled to intracellular calcium mobilization. Exposure of these cells to Ang II induced several short and long growth-related metabolic events mediated by the AT1 receptor, including c-fos gene expression, changes in cell cycle and cell proliferation. Activation of interstitial fibroblasts by Ang II could also contribute to extracellular matrix accumulation. Stimulation with Ang II increased mRNA expression of TGF-beta 1, fibronectin and type I collagen. In fact, Ang II enhanced fibronectin production via AT1 receptors by a process depending on autocrine TGF-beta secretion. The mechanism of some Ang II actions (calcium mobilization and fibronectin production) depended on protein kinase C and tyrosine kinase activation. We further investigated whether renal fibroblasts could express some components of the renin-angiotensin system. These cells constitutively expressed the angiotensinogen gene that was up-regulated by Ang II. Collectively, these results indicate that in renal interstitial fibroblasts Ang II causes hyperplasia and extracellular matrix production via the AT1 receptor. Ang II may initiate a positive feedback regulation of fibroblasts growth, inducing the expression of TGF-beta 1 and angiotensinogen genes. Ang II, acting directly on interstitial fibroblasts, may be implicated in the pathogenesis of renal fibrosis.
肾素-血管紧张素系统似乎在肾间质纤维化的发病机制中起重要作用。然而，血管紧张素II（Ang II）对培养的肾成纤维细胞的潜在直接作用研究较少。我们观察到大鼠肾间质成纤维细胞（NRK 49F细胞系）具有与细胞内钙动员偶联的AT1受体。将这些细胞暴露于Ang II会诱导由AT1受体介导的几种短期和长期的生长相关代谢事件，包括c-fos基因表达、细胞周期变化和细胞增殖。Ang II激活间质成纤维细胞也可能导致细胞外基质积累。用Ang II刺激可增加TGF-β1、纤连蛋白和I型胶原的mRNA表达。事实上，Ang II通过依赖自分泌TGF-β分泌的过程，经由AT1受体增强纤连蛋白的产生。一些Ang II作用（钙动员和纤连蛋白产生）的机制取决于蛋白激酶C和酪氨酸激酶的激活。我们进一步研究了肾成纤维细胞是否能表达肾素-血管紧张素系统的某些成分。这些细胞组成性表达血管紧张素原基因，该基因被Ang II上调。总的来说，这些结果表明在肾间质成纤维细胞中，Ang II通过AT1受体导致细胞增生和细胞外基质产生。Ang II可能启动成纤维细胞生长的正反馈调节，诱导TGF-β1和血管紧张素原基因的表达。直接作用于间质成纤维细胞的Ang II可能与肾纤维化的发病机制有关。
