Department of Nephrology, University Hospital Freiburg, Freiburg, Germany.
Kidney Int. 2011 Mar;79(5):502-11. doi: 10.1038/ki.2010.457. Epub 2010 Nov 17.
The immunosuppressive drug rapamycin has helped to identify a large signaling network around the target of rapamycin (TOR) protein that integrates information on nutrient availability and growth factors to control protein synthesis and cell size. Studies using rapamycin in animal models of kidney disease indicate that mTOR deregulation has a role in glomerular disease, polycystic kidney disease, and renal cancer. The role of mTOR activation in podocytes is context dependent, and indirect evidence suggests that mTOR may have a role in chronic podocyte loss. Several lines of evidence show that cyst formation in polycystic kidney disease (PKD) involves mTOR activation and its upstream regulator TSC. Polycystin 1 regulates mTOR activity through different pathways, and TSC intersects with the primary cilium, a crucial cell organelle in the pathogenesis of PKD. Data from hamartoma syndromes provide clear evidence that mutation of members of the mTOR network results in renal cancers. The detailed analysis of renal cell carcinomas has revealed a positive feedback loop involving VHL and mTOR. Rapamycin and its derivatives have been approved for the treatment of advanced renal cancer and are being investigated for the treatment of PKD. Discrepancies exist between the effects of rapamycin in animal models and the clinical experience with patients, precluding the widespread use of mTOR inhibitors in kidney disease. The details of mTOR signaling in the kidney need to be clarified to hopefully develop targeted treatments for renal disease in the future.
免疫抑制药物雷帕霉素有助于确定雷帕霉素（TOR）蛋白的目标周围的大型信号网络，该网络整合了有关营养物质可用性和生长因子的信息，以控制蛋白质合成和细胞大小。在肾脏病动物模型中使用雷帕霉素的研究表明，mTOR 失调在肾小球疾病、多囊肾病和肾细胞癌中起作用。mTOR 在足细胞中的激活作用具有上下文依赖性，间接证据表明 mTOR 可能在慢性足细胞丢失中起作用。有几条证据表明，多囊肾病（PKD）中的囊肿形成涉及 mTOR 激活及其上游调节剂 TSC。多囊蛋白 1 通过不同途径调节 mTOR 活性，而 TSC 与初级纤毛相交，初级纤毛是 PKD 发病机制中的关键细胞细胞器。来自错构瘤综合征的资料提供了明确的证据，表明 mTOR 网络成员的突变导致肾细胞癌。对肾细胞癌的详细分析揭示了涉及 VHL 和 mTOR 的正反馈回路。雷帕霉素及其衍生物已被批准用于治疗晚期肾细胞癌，并正在研究用于治疗 PKD。雷帕霉素在动物模型中的作用与患者的临床经验之间存在差异，这排除了 mTOR 抑制剂在肾脏病中的广泛应用。需要阐明肾脏中 mTOR 信号的细节，以期在未来为肾脏疾病开发靶向治疗。
