Mamenko M, Zaika O, Boukelmoune N, O'Neil R G, Pochynyuk O
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, Texas.
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, Texas
Am J Physiol Renal Physiol. 2015 Feb 15;308(4):F275-86. doi: 10.1152/ajprenal.00485.2014. Epub 2014 Dec 10.
Long-standing experimental evidence suggests that epithelial cells in the renal tubule are able to sense osmotic and pressure gradients caused by alterations in ultrafiltrate flow by elevating intracellular Ca(2+) concentration. These responses are viewed as critical regulators of a variety of processes ranging from transport of water and solutes to cellular growth and differentiation. A loss in the ability to sense mechanical stimuli has been implicated in numerous pathologies associated with systemic imbalance of electrolytes and to the development of polycystic kidney disease. The molecular mechanisms conferring mechanosensitive properties to epithelial tubular cells involve activation of transient receptor potential (TRP) channels, such as TRPV4, allowing direct Ca(2+) influx to increase intracellular Ca(2+) concentration. In this review, we critically analyze the current evidence about signaling determinants of TRPV4 activation by luminal flow in the distal nephron and discuss how dysfunction of this mechanism contributes to the progression of polycystic kidney disease. We also review the physiological relevance of TRPV4-based mechanosensitivity in controlling flow-dependent K(+) secretion in the distal renal tubule.
长期的实验证据表明，肾小管中的上皮细胞能够通过提高细胞内钙离子浓度来感知由超滤液流量变化引起的渗透压和压力梯度。这些反应被视为从水和溶质运输到细胞生长和分化等各种过程的关键调节因子。机械刺激感知能力的丧失与许多与电解质全身失衡相关的疾病以及多囊肾病的发展有关。赋予上皮管状细胞机械敏感特性的分子机制涉及瞬时受体电位（TRP）通道的激活，如TRPV4，允许钙离子直接内流以增加细胞内钙离子浓度。在这篇综述中，我们批判性地分析了目前关于远端肾单位中管腔流量激活TRPV4的信号决定因素的证据，并讨论了该机制功能障碍如何导致多囊肾病的进展。我们还综述了基于TRPV4的机械敏感性在控制远端肾小管中流量依赖性钾离子分泌方面的生理相关性。
