MATURATION OF CATION TRANSPORT IN DISTAL NEPHRON

描述(改编自申请人的摘要)：最终规则 尿K+和Na+排泄在肾皮质完成 收集管道(CCC)。在这个节段，尿Na+扩散到主体 细胞通过心尖Na+通道(ENaCs)，在基底外侧被挤出 膜被Na-K泵吸收以换取K+。单元格K+然后 在有利的电化学梯度下被动地扩散出电池 通过心尖K+选择性(SK)通道进入管腔液体。肾脏 足月新生儿有效地保留尿液中的K+和Na+ 为了增长。与观察到的高净K+分泌率相比， 从成年动物分离的CCDs和体外微灌流，片段来自 新生动物没有明显的K+转运和顶端SK的缺乏 频道。然而，相同的新生儿节段拥有传导ENaC通道 吸收Na+的速度是成人的一半。这件事的重点是 应用是研究细胞和分子机制的调节 心尖5K和ENaC通道的出生后激活，那些限速的通道 细胞内K+、Na+转运途径的研究。我们提出的假设 检查它们与SK(特定目标1)和Na+(特定目标2)的关系 频道，首先关注的是辨别是否出现了 传导通道受转录、翻译和/或 翻译后处理。此后，我们将确定 循环(肾上腺皮质类固醇)和胞浆(激动酶、钙离子) 调节基因和蛋白质表达的生命早期流行的因子。 离子通道活性，以及发育中的电荷耦合器件中的小管运输。这些 研究将使用分子， 电生理学和功能技术。这样做的长期目标是 研究的目的是确定细胞和分子机制 Na~+、K~+转运的调节和相互作用 手机。这些研究应该有助于我们理解 与电解质失衡相关的遗传性和获得性疾病， 发病率很高的疾病。

DESCRIPTION (Adapted from the Applicant's Abstract): The final regulation of urinary K+ and Na+ excretion is accomplished in the renal cortical collecting duct (CCC). In this segment, urinary Na+ diffuses into principal cells through apical Na+ channels (ENaCs) and is extruded at the basolateral membrane in exchange for uptake of K+ by the Na-K pump. Cell K+ then passively diffuses out of the cell down a favorable electrochemical gradient into the luminal fluid through apical K+-selective (SK) channels. Kidneys of full term neonates efficiently retain urinary K+ and Na+, as is necessary for growth. In contrast to the high rates of net K+ secretion observed in CCDs isolated from adult animals and microperfused in vitro, segments from neonatal animals show no significant K+ transport and a paucity of apical SK channels. Yet, the same neonatal segments possess conducting ENaC channels and absorb Na+ at a rate half that measured in the adult. The focus of this application is to examine the cellular and molecular mechanisms mediating the postnatal activation of apical 5K and ENaC channels, those rate-limiting pathways for K+ and Na+ transport in the CCD. The hypotheses we propose to examine, as they relate to the SK (Specific Aim 1) and Na+ (Specific Aim 2) channel, are focussed first on discerning whether the appearance of conducting channels is regulated by transcription, translation, and/or post-translational processing. Thereafter, we will identify those circulating (adrenal corticosteroids) and cytoplasmic (kinases, Ca2+) factors prevailing early in life that regulate gene and protein expression. ion channel activity, and tubular transport in the developing CCD. These studies will be accomplished using a combination of molecular, electrophysiologic, and functional techniques. The long-term goal of this study is to identify the cellular and molecular mechanisms responsible for the regulation and interaction of Na+ and K+ transport in the principal cell. These studies should help us understand the physiologic basis for inherited and acquired disorders associated with electrolyte imbalance, disorders which carry a high morbidity.