Schild Laurent
Departement de Pharmacologie and Toxicologie, Universite de Lausanne, Lausanne, Switzerland.
Biochim Biophys Acta. 2010 Dec;1802(12):1159-65. doi: 10.1016/j.bbadis.2010.06.014. Epub 2010 Jun 27.
Studies aiming at the elucidation of the genetic basis of rare monogenic forms of hypertension have identified mutations in genes coding for the epithelial sodium channel ENaC, for the mineralocorticoid receptor, or for enzymes crucial for the synthesis of aldosterone. These genetic studies clearly demonstrate the importance of the regulation of Na(+) absorption in the aldosterone-sensitive distal nephron (ASDN), for the maintenance of the extracellular fluid volume and blood pressure. Recent studies aiming at a better understanding of the cellular and molecular basis of ENaC-mediated Na(+) absorption in the distal part of nephron, have essentially focused on the regulation ENaC activity and on the aldosterone-signaling cascade. ENaC is a constitutively open channel, and factors controlling the number of active channels at the cell surface are likely to have profound effects on Na(+) absorption in the ASDN, and in the amount of Na(+) that is excreted in the final urine. A number of membrane-bound proteases, kinases, have recently been identified that increase ENaC activity at the cell surface in heterologous expressions systems. Ubiquitylation is a general process that regulates the stability of a variety of target proteins that include ENaC. Recently, deubiquitylating enzymes have been shown to increase ENaC activity in heterologous expressions systems. These regulatory mechanisms are likely to be nephron specific, since in vivo studies indicate that the adaptation of the renal excretion of Na(+) in response to Na(+) diet occurs predominantly in the early part (the connecting tubule) of the ASDN. An important work is presently done to determine in vivo the physiological relevance of these cellular and molecular mechanisms in regulation of ENaC activity. The contribution of the protease-dependent ENaC regulation in mediating Na(+) absorption in the ASDN is still not clearly understood. The signaling pathway that involves ubiquitylation of ENaC does not seem to be absolutely required for the aldosterone-mediated control of ENaC. These in vivo physiological studies presently constitute a major challenge for our understanding of the regulation of ENaC to maintain the Na(+) balance.
旨在阐明罕见单基因形式高血压遗传基础的研究，已确定了编码上皮钠通道ENaC、盐皮质激素受体或醛固酮合成关键酶的基因突变。这些遗传学研究清楚地表明，醛固酮敏感远端肾单位（ASDN）中钠（Na⁺）重吸收的调节对于维持细胞外液容量和血压至关重要。最近旨在更好地理解肾单位远端ENaC介导的Na⁺重吸收的细胞和分子基础的研究，主要集中在ENaC活性调节和醛固酮信号级联反应上。ENaC是一个持续开放的通道，控制细胞表面活性通道数量的因素可能对ASDN中的Na⁺重吸收以及最终尿液中排出的Na⁺量产生深远影响。最近已鉴定出一些膜结合蛋白酶、激酶，它们在异源表达系统中可增加细胞表面的ENaC活性。泛素化是一个普遍过程，可调节包括ENaC在内的多种靶蛋白的稳定性。最近，去泛素化酶已被证明可在异源表达系统中增加ENaC活性。这些调节机制可能具有肾单位特异性，因为体内研究表明，肾对Na⁺饮食的排泄适应主要发生在ASDN的早期部分（连接小管）。目前正在进行重要工作，以确定这些细胞和分子机制在体内对ENaC活性调节的生理相关性。蛋白酶依赖性ENaC调节在介导ASDN中Na⁺重吸收方面的作用仍未完全清楚。涉及ENaC泛素化的信号通路似乎并非醛固酮介导的ENaC控制绝对必需的。目前这些体内生理学研究对我们理解ENaC调节以维持Na⁺平衡构成了重大挑战。
