Mammalian target of rapamycin and caspase inhibitors in polycystic kidney disease
Mammalian target of rapamycin and caspase inhibitors in polycystic kidney disease
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DOI：
10.2215/cjn.05611207
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发表时间：
2008-07-01
影响因子：
9.8
通讯作者：
Edelstein, Charles L.
中科院分区：
文献类型：
--
作者：
Edelstein, Charles L.
衬在囊肿以及非囊性肾小管上皮细胞的肾小管上皮细胞的最重要的异常之一是肾小管细胞增殖和凋亡之间的平衡紊乱。雷帕霉素信号通路的哺乳动物靶标的激活导致细胞增殖增加。最近的研究表明，哺乳动物雷帕霉素靶蛋白信号通路在多囊肾病中存在异常。西罗莫司或依维莫司抑制雷帕霉素的哺乳动物靶点导致多囊肾病大鼠和小鼠模型中囊肿形成的减弱。细胞凋亡是大多数多囊肾疾病模型的病理特征，包括人类多囊肾。细胞凋亡的主要介质半胱天冬酶在多囊肾病肾脏中增加。体外和体内研究均表明，胱天蛋白酶或细胞凋亡抑制可减弱囊肿形成。本文综述了哺乳动物靶向雷帕霉素和细胞凋亡信号通路在多囊肾疾病中的作用，以及哺乳动物靶向雷帕霉素抑制剂和细胞凋亡抑制剂作为减少囊肿形成的潜在疗法的作用。
One of the most important abnormalities of the tubular epithelial cells lining the cysts as well as noncystic tubular epithelium is a disturbance in the balance between tubular cell proliferation and apoptosis. Activation of the mammalian target of rapamycin signaling pathway results in increased cell proliferation. Recent studies suggested abnormalities of the mammalian target of rapamycin signaling pathway in polycystic kidney disease. Mammalian target of rapamycin inhibition with sirolimus or everolimus results in attenuation of cyst formation in rat and mouse models of polycystic kidney disease. Apoptosis is a pathologic feature of most models of polycystic kidney disease, including human polycystic kidneys. Caspases, the major mediators of apoptosis, are increased in polycystic kidney disease kidneys. Both in vitro and in vivo studies suggest that caspase or apoptosis inhibition attenuates cyst formation. This review focuses on mammalian target of rapamycin and apoptosis signaling pathways in polycystic kidney disease and the role of mammalian target of rapamycin inhibitors and apoptosis inhibitors as potential therapies to reduce cyst formation.