Triptolide is a traditional Chinese medicine-derived inhibitor of polycystic kidney disease
Triptolide is a traditional Chinese medicine-derived inhibitor of polycystic kidney disease
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DOI：
10.1073/pnas.0700499104
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发表时间：
2007-03-13
影响因子：
11.1
通讯作者：
Crews, Craig M.
中科院分区：
文献类型：
--
作者：
Leuenroth, Stephanie J.;Okuhara, Dayne;Crews, Craig M.
在肾脏器官发生过程中，肾小管上皮细胞不断增殖，直到形成一个功能性小管，这是纤毛弯曲对液体流动的反应。这种流诱导的纤毛机械感觉开放钙(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或其调控蛋白多囊蛋白-1(PC1)的缺失或突变导致常染色体显性遗传性多囊肾病(ADPKD)，其特征是囊性形成和生长，常导致肾功能衰竭和死亡。在这里，我们发现雷公藤中的活性二萜雷公藤甲素通过PC2依赖机制诱导钙释放。此外，在ADPKD的小鼠模型中，雷公藤甲素通过恢复这些细胞中的钙信号，阻止了细胞的增殖，并减少了整个囊泡的形成。我们预计，小分子诱导PC2依赖的钙释放可能是ADPKD的有效治疗策略。
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 (Ca2+) 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 Ca2+ release by a PC2-dependent mechanism. Furthermore, in a murine model of ADPKD, triptolide arrests cellular proliferation and attenuates overall cyst formation by restoring Ca2+ 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.