Leuenroth Stephanie J, Okuhara Dayne, Shotwell Joseph D, Markowitz Glen S, Yu Zhiheng, Somlo Stefan, Crews Craig M
Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA.
Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4389-94. doi: 10.1073/pnas.0700499104. Epub 2007 Mar 6.
During kidney organogenesis, tubular epithelial cells proliferate until a functional tubule is formed as sensed by cilia bending in response to fluid flow. This flow-induced ciliary mechanosensation opens the calcium (Ca(2+)) channel polycystin-2 (PC2), resulting in a calcium flux-mediated cell cycle arrest. Loss or mutation of either PC2 or its regulatory protein polycystin-1 (PC1) results in autosomal dominant polycystic kidney disease (ADPKD), characterized by cyst formation and growth and often leading to renal failure and death. Here we show that triptolide, the active diterpene in the traditional Chinese medicine Lei Gong Teng, induces Ca(2+) release by a PC2-dependent mechanism. Furthermore, in a murine model of ADPKD, triptolide arrests cellular proliferation and attenuates overall cyst formation by restoring Ca(2+) signaling in these cells. We anticipate that small molecule induction of PC2-dependent calcium release is likely to be a valid therapeutic strategy for ADPKD.
在肾脏器官发生过程中，肾小管上皮细胞不断增殖，直到形成一条功能性肾小管，这一过程是由纤毛响应液流弯曲而感知到的。这种液流诱导的纤毛机械感觉打开了钙（Ca(2+)）通道多囊蛋白-2（PC2），导致钙通量介导的细胞周期停滞。PC2或其调节蛋白多囊蛋白-1（PC1）的缺失或突变会导致常染色体显性多囊肾病（ADPKD），其特征是囊肿形成和生长，常导致肾衰竭和死亡。在此我们表明，中药雷公藤中的活性二萜化合物雷公藤内酯醇通过一种依赖PC2的机制诱导Ca(2+)释放。此外，在ADPKD小鼠模型中，雷公藤内酯醇通过恢复这些细胞中的Ca(2+)信号传导来阻止细胞增殖并减弱整体囊肿形成。我们预计，小分子诱导依赖PC2的钙释放可能是治疗ADPKD的一种有效策略。
