Institut de Pharmacologie Moléculaire et Cellulaire, UMR CNRS 7275, Université de Nice Sophia Antipolis, 06560 Valbonne, France.
Cell Rep. 2012 Mar 29;1(3):241-50. doi: 10.1016/j.celrep.2012.01.006. Epub 2012 Mar 8.
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 mechanism is at play in other important pathologies associated with apoptosis and in which pressure or flow stimulation is altered, including heart failure or atherosclerosis.
目前，人们对于肾脏上皮细胞如何应对压力增加以及其与肾脏疾病状态的联系还知之甚少。Pkd1 基因敲除或表达模拟常染色体显性多囊肾病的 PC2 致病突变体，可显著增强机械应激诱导的管状细胞凋亡。我们发现，在近端曲管上皮细胞中存在一种依赖 TREK-2 K(2P)亚基的张力激活型 K(+)通道。我们的研究结果进一步表明，多囊蛋白可保护肾脏上皮细胞免受机械应激诱导的细胞凋亡，而这种功能是通过打开张力激活的 K(2P)通道来介导的。因此，据我们所知，我们首次在体外和体内建立了机械转导与机械保护之间的功能关系。我们提出，这种机制在与凋亡相关的其他重要病理中起作用，这些病理与压力或流量刺激改变有关，包括心力衰竭或动脉粥样硬化。
