Mammalian target of rapamycin inhibition in polycystic kidney disease: From bench to bedside.
Mammalian target of rapamycin inhibition in polycystic kidney disease: From bench to bedside.
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DOI：
10.1016/j.krcp.2012.07.002
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发表时间：
2012-09
影响因子：
3
通讯作者：
Edelstein CL
中科院分区：
文献类型：
--
作者：
Kim HJ;Edelstein CL
常染色体显性遗传性多囊肾病（ADPKD）是美国最常见的危及生命的遗传性疾病，可导致慢性肾病，需要透析和移植。大约85%的ADPKD病例是由编码多囊蛋白-1（一种大型膜受体）的Pkd 1基因突变引起的。Pkd 1基因突变导致肾小管上皮细胞异常增殖，这在PKD的囊肿发育和/或生长中起关键作用。在啮齿动物和人类的多囊性肾中已经证实了增殖性哺乳动物雷帕霉素靶蛋白（mTOR）信号通路的激活。西罗莫司或依维莫司抑制mTOR可减少大多数PKD动物模型中的囊肿，包括人类疾病的Pkd 1和Pkd 2基因缺陷型原位杂交模型。在动物研究的基础上，进行了人体研究。新英格兰医学杂志上发表的两项关于依维莫司或西罗莫司治疗ADPKD患者的大型随机临床试验非常不起眼，且副作用较高。人类研究不引人注目的可能原因包括其持续时间短，脱落率高，次优剂量，缺乏“快速”和“缓慢进展者”的随机化以及ADPKD中肾脏大小和肾功能之间缺乏相关性。未来的mTOR抑制ADPKD进行了讨论。
Autosomal dominant polycystic kidney disease (ADPKD) is the most common life-threatening hereditary disease in the USA resulting in chronic kidney disease and the need for dialysis and transplantation. Approximately 85% of cases of ADPKD are caused by a mutation in the Pkd1 gene that encodes polycystin-1, a large membrane receptor. The Pkd1 gene mutation results in abnormal proliferation in tubular epithelial cells, which plays a crucial role in cyst development and/or growth in PKD. Activation of the proliferative mammalian target of rapamycin (mTOR) signaling pathway has been demonstrated in polycystic kidneys from rodents and humans. mTOR inhibition with sirolimus or everolimus decreases cysts in most animal models of PKD including Pkd1 and Pkd2 gene deficient orthologous models of human disease. On the basis of animal studies, human studies were undertaken. Two large randomized clinical trials published in the New England Journal of Medicine of everolimus or sirolimus in ADPKD patients were very unimpressive and associated with a high side-effect profile. Possible reasons for the unimpressive nature of the human studies include their short duration, the high drop-out rate, suboptimal dosing, lack of randomization of “fast” and “slow progressors” and the lack of correlation between kidney size and kidney function in ADPKD. The future of mTOR inhibition in ADPKD is discussed.