MATURATION OF CATION TRANSPORT IN DISTAL NEPHRON

描述（改编自申请人摘要）：最终法规 尿中K+和Na+的排泄是在肾皮质完成的 收集管（CCC）。 在这一段，尿Na+扩散到主要的 细胞通过顶端Na+通道（ENaCs），并在基底外侧被挤出 通过Na-K泵交换K+的吸收。 K+细胞， 沿着有利的电化学梯度被动地扩散出电池 通过顶端K+选择性（SK）通道进入腔液。 肾脏 的足月新生儿有效地保留尿K+和Na+，这是必要的 促进增长。 与高速率的净K+分泌相比， 从成年动物中分离并在体外进行微灌注的CCD， 新生动物没有明显的K+转运和缺乏顶端SK 渠道 然而，相同的新生儿节段具有传导ENaC通道， 吸收Na+的速度只有成人的一半 的重点 应用程序是检查细胞和分子机制介导的 出生后顶端5 K和ENaC通道的激活，这些通道是限速的， CCD中K+和Na+转运的途径。 我们提出的假设 检查，因为它们与SK（特定目标1）和Na+（特定目标2）有关 通道，首先集中在辨别是否出现 传导通道通过转录、翻译和/或 翻译后加工 之后，我们将确定这些 循环（肾上腺皮质类固醇）和细胞质（激酶，Ca 2+） 在生命早期普遍存在的调节基因和蛋白质表达的因素。 离子通道活性和管状运输在发展CCD。 这些 研究将使用分子， 电生理学和功能技术。 其长期目标是 研究的目的是确定细胞和分子机制， Na ~+和K ~+转运的调节和相互作用 cell. 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.