Departamento de Fisiología y Farmacología, Instituto Reina Sofía de Investigación Nefrológica, Universidad de Salamanca, Salamanca 37007, Spain.
Kidney Int. 2010 Mar;77(6):509-18. doi: 10.1038/ki.2009.498. Epub 2009 Dec 23.
Tubulointerstitial fibrosis is characterized by the presence of myofibroblasts that contribute to extracellular matrix accumulation. These cells may originate from resident fibroblasts, bone-marrow-derived cells, or renal epithelial cells converting to a mesenchymal phenotype. Ras GTPases are activated during renal fibrosis and play crucial roles in regulating both cell proliferation and TGF-beta-induced epithelial-mesenchymal transition. Here we set out to assess the contribution of Ras to experimental renal fibrosis using the well-established model of unilateral ureteral obstruction. Fifteen days after obstruction, both fibroblast proliferation and inducers of epithelial-mesenchymal transition were lower in obstructed kidneys of H-ras knockout mice and in fibroblast cell lines derived from these mice. Interestingly, fibronectin, collagen I accumulation, overall interstitial fibrosis, and the myofibroblast population were also lower in the knockout than in the wild-type mice. As expected, we found lower levels of activated Akt in the kidneys and cultured fibroblasts of the knockout. Whether Ras inhibition will turn out to prevent progression of renal fibrosis will require more direct studies.
肾小管间质纤维化的特征是肌成纤维细胞的存在，肌成纤维细胞有助于细胞外基质的积累。这些细胞可能来源于固有成纤维细胞、骨髓来源的细胞或肾上皮细胞向间充质表型的转化。Ras GTPases 在肾纤维化过程中被激活，在调节细胞增殖和 TGF-β诱导的上皮-间充质转化方面发挥着关键作用。在这里，我们使用单侧输尿管梗阻这一成熟的模型来评估 Ras 对实验性肾纤维化的贡献。在梗阻后 15 天，H-ras 基因敲除小鼠和源自这些小鼠的成纤维细胞系的梗阻侧肾脏中的成纤维细胞增殖和上皮-间充质转化诱导物的水平均降低。有趣的是，基因敲除小鼠的纤维连接蛋白、胶原 I 积累、整体间质纤维化和肌成纤维细胞数量也低于野生型小鼠。正如预期的那样，我们在基因敲除的肾脏和培养的成纤维细胞中发现 Akt 的激活水平较低。Ras 抑制是否会阻止肾纤维化的进展还需要更直接的研究。
