Loss of Tsc1, but not Pten, in renal tubular cells causes polycystic kidney disease by activating mTORC1
Loss of Tsc1, but not Pten, in renal tubular cells causes polycystic kidney disease by activating mTORC1
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DOI：
10.1093/hmg/ddp398
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发表时间：
2009-11-15
影响因子：
3.5
通讯作者：
Parada, Luis F.
中科院分区：
文献类型：
--
作者：
Zhou, Jing;Brugarolas, James;Parada, Luis F.
结节性硬化症复合体 (TSC) 是一种与 TSC1 或 TSC2 基因突变相关的遗传性疾病，该基因编码的蛋白质形成复合物，对哺乳动物雷帕霉素复合物靶标 1 (mTORC1) 进行负调控。临床上，一小部分TSC患者会发展为严重的婴儿多囊肾病（PKD），这被认为是由人类16号染色体上连续的TSC2和PKD1基因缺失引起的。最近的研究表明TSC/mTORC1信号通路与PKD有关，但TSC/mTORC1通路功能障碍如何诱发PKD尚不清楚。我们报告了通过敲除肾小管细胞子集中的 Tsc1 创建的 PKD 小鼠模型。这些小鼠中广泛的肾囊肿形成伴随着细胞自主区室和非细胞自主区室中 mTORC1 活性的广泛升高。此外，囊肿发育需要 mTORC1 激活，因为低剂量的雷帕霉素给药可有效阻止囊肿形成。有趣的是，在同一细胞中，TSC1/TSC2 的上游调节因子 Pten 的破坏似乎不会导致 PKD，因为 mTORC1 的激活有限，这表明 PTEN 可能不是出生后早期肾脏发育过程中 TSC/mTORC1 的主要上游调节因子。
Tuberous sclerosis complex (TSC) is a genetic disorder linked to mutations of either the TSC1 or TSC2 gene, which encode proteins that form a complex to negatively regulate mammalian target of rapamycin complex 1 (mTORC1). Clinically, a small percentage of TSC patients develop severe infantile polycystic kidney disease (PKD), which is believed to be caused by deletion of the contiguous TSC2 and PKD1 genes on human chromosome 16. Recent studies have implicated the TSC/mTORC1 signaling pathway in PKD, but how dysfunction of the TSC/mTORC1 pathway induces PKD is not clear. We report a PKD mouse model created by knocking out Tsc1 in a subset of renal tubular cells. Extensive renal cyst formation in these mice is accompanied by broadly elevated mTORC1 activity in both cell autonomous and non-cell autonomous compartments. Furthermore, cyst development requires mTORC1 activation, as low dosage of rapamycin administration effectively blocks cyst formation. Interestingly, disruption of Pten, an upstream regulator of TSC1/TSC2, in the same cells, does not lead to PKD seemingly due to limited activation of mTORC1, suggesting that PTEN may not be a major upstream regulator of TSC/mTORC1 during early postnatal kidney development.