Sherpa Rinzhin T, Atkinson Kimberly F, Ferreira Viviana P, Nauli Surya M
Department of Biomedical & Pharmaceutical Sciences, Chapman University, Irvine, CA.
Department of Medical Microbiology and Immunology, University of Toledo, Toledo, OH.
Int Educ Res J. 2016 Dec;2(12):91-97.
Primary cilia arebiophysically-sensitive organelles responsible for sensing fluid-flow and transducing this stimulus into intracellular responses. Previous studies have shown that the primary cilia mediate flow-induced calcium influx, and sensitivity of cilia function to flow is correlated to cilia length. Cells with abnormal cilia length or function can lead to a host of diseases that are collectively termed as ciliopathies. Rapamycin, a potent inhibitor of mTOR (mammalian target of rapamycin), has been demonstrated to be a potential pharmacological agent against the aberrant mTOR signaling seen in ciliopathies such as polycystic kidney disease (PKD) and tuberous sclerosis complex (TSC). Here we look at the effects of rapamycin on ciliary length and function for the first time. Compared to controls, primary cilia in rapamycin-treated porcine renal epithelial and mouse vascular endothelial cells showed a significant increase in length. Graded increases in fluid-shear stress further indicates that rapamycin enhances cilia sensitivity to fluid flow. Treatment with rapamycin led to G0 arrest in porcine epithelial cells while no significant change in cell cycle were observed in rapamycin-treated mouse epithelial or endothelial cells, indicating a species-specific effect of rapamycin. Given the previousin vitro and in vivo studies establishing rapamycin as a potential therapeutic agent for ciliopathies, such as PKD and TSC, our studies show that rapamycin enhances ciliary function and sensitivity to fluid flow. The results of our studies suggest a potential ciliotherapeutic effect of rapamycin.
初级纤毛是生物物理敏感细胞器，负责感知流体流动并将这种刺激转化为细胞内反应。先前的研究表明，初级纤毛介导流动诱导的钙内流，并且纤毛功能对流动的敏感性与纤毛长度相关。纤毛长度或功能异常的细胞会导致一系列统称为纤毛病的疾病。雷帕霉素是一种有效的mTOR（哺乳动物雷帕霉素靶蛋白）抑制剂，已被证明是一种潜在的药物，可对抗在多囊肾病（PKD）和结节性硬化症（TSC）等纤毛病中出现的异常mTOR信号传导。在这里，我们首次研究了雷帕霉素对纤毛长度和功能的影响。与对照组相比，雷帕霉素处理的猪肾上皮细胞和小鼠血管内皮细胞中的初级纤毛长度显著增加。流体剪切应力的分级增加进一步表明雷帕霉素增强了纤毛对流体流动的敏感性。雷帕霉素处理导致猪上皮细胞停滞在G0期，而在雷帕霉素处理的小鼠上皮细胞或内皮细胞中未观察到细胞周期的显著变化，这表明雷帕霉素具有物种特异性作用。鉴于先前的体外和体内研究将雷帕霉素确立为PKD和TSC等纤毛病的潜在治疗药物，我们的研究表明雷帕霉素增强了纤毛功能和对流体流动的敏感性。我们的研究结果表明雷帕霉素具有潜在的纤毛治疗作用。
