Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA 93106-9610, USA.
J Am Soc Nephrol. 2010 Mar;21(3):489-97. doi: 10.1681/ASN.2009040421. Epub 2010 Jan 14.
Aberrant activation of the mammalian target of rapamycin (mTOR) pathway occurs in polycystic kidney disease (PKD). mTOR inhibitors, such as rapamycin, are highly effective in several rodent models of PKD, but these models result from mutations in genes other than Pkd1 and Pkd2, which are the primary genes responsible for human autosomal dominant PKD. To address this limitation, we tested the efficacy of rapamycin in a mouse model that results from conditional inactivation of Pkd1. Mosaic deletion of Pkd1 resulted in PKD and replicated characteristic features of human PKD including aberrant mTOR activation, epithelial proliferation and apoptosis, and progressive fibrosis. Treatment with rapamycin was highly effective: It reduced cyst growth, preserved renal function, inhibited epithelial cell proliferation, increased apoptosis of cyst-lining cells, and inhibited fibrosis. These data provide in vivo evidence that rapamycin is effective in a human-orthologous mouse model of PKD.
哺乳动物雷帕霉素靶蛋白（mTOR）途径的异常激活发生在多囊肾病（PKD）中。雷帕霉素等 mTOR 抑制剂在几种 PKD 的啮齿动物模型中非常有效，但这些模型是由 Pkd1 和 Pkd2 以外的基因突变引起的，而 Pkd1 和 Pkd2 是导致常染色体显性遗传 PKD 的主要基因。为了解决这一限制，我们在一种由 Pkd1 条件性失活引起的小鼠模型中测试了雷帕霉素的疗效。Pkd1 的镶嵌缺失导致 PKD，并复制了人类 PKD 的特征，包括异常的 mTOR 激活、上皮细胞增殖和凋亡以及进行性纤维化。雷帕霉素治疗非常有效：它减少了囊肿生长，保留了肾功能，抑制了上皮细胞增殖，增加了囊壁细胞的凋亡，并抑制了纤维化。这些数据提供了体内证据，表明雷帕霉素在人类同源的 PKD 小鼠模型中有效。
