Mechanoprotection by Polycystins against Apoptosis Is Mediated through the Opening of Stretch-Activated K2P Channels
Mechanoprotection by Polycystins against Apoptosis Is Mediated through the Opening of Stretch-Activated K2P Channels
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DOI：
10.1016/j.celrep.2012.01.006
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发表时间：
2012-03-01
期刊：
影响因子：
8.8
通讯作者：
Duprat, Fabrice
中科院分区：
文献类型：
--
作者：
Peyronnet, Remi;Sharif-Naeini, Reza;Duprat, Fabrice
肾上皮细胞如何对增加的压力做出反应以及与肾脏疾病状态的联系仍然知之甚少。Pkd 1敲除或表达PC 2致病突变体，模仿常染色体显性多囊肾病，显著增强机械应力诱导的肾小管凋亡细胞死亡。我们显示存在一个依赖于TREK-2 K-2 P亚基在近曲小管上皮细胞的拉伸激活的K+通道。我们的研究结果进一步表明，多囊蛋白保护肾上皮细胞对凋亡的机械应力的反应，这一功能是通过开放的拉伸激活的K-2 P通道介导的。因此，据我们所知，我们第一次建立，在体外和体内，机械转导和机械保护之间的功能关系。我们认为这种机制在其他与细胞凋亡相关的重要病理中起作用，其中压力或流量刺激被改变，包括心力衰竭或动脉粥样硬化。
How renal epithelial cells respond to increased pressure and the link with kidney disease states remain poorly understood. Pkd1 knockout or expression of a PC2 pathogenic mutant, mimicking the autosomal dominant polycystic kidney disease, dramatically enhances mechanical stress-induced tubular apoptotic cell death. We show the presence of a stretch-activated K+ channel dependent on the TREK-2 K-2P subunit in proximal convoluted tubule epithelial cells. Our findings further demonstrate that polycystins protect renal epithelial cells against apoptosis in response to mechanical stress, and this function is mediated through the opening of stretch-activated K-2P channels. Thus, to our knowledge, we establish for the first time, both in vitro and in vivo, a functional relationship between mechanotransduction and mechanoprotection. We propose that this mechanismis at play in other important pathologies associated with apoptosis and in which pressure or flow stimulation is altered, including heart failure or atherosclerosis.