Epithelial Na Channels and Regulation of Na Excretion

描述(申请人提供)：上皮钠通道表达于 哺乳动物肾单位的远端部分，已知受 肾素-血管紧张素-醛固酮轴。这些渠道的作用及其 盐皮质激素对每日钠排泄的调节作用 将对肾脏进行检查。初步数据表明，当老鼠 在给予低钠饮食的情况下，他们可以在15分钟内调节肾脏钠的排泄 几个小时，钠通道重吸收的增加可以解释 减少的排泄率中的很大一部分。我们将评估 不同程度钠耗竭的通道，测量两个通道 活动度和总尿钠排泄量。渠道活动将按以下方式衡量 肾皮质集合管对阿米洛利敏感的全细胞电流 以及髓集合管和连接小管 量化其对肾脏钠转运的贡献。我们将进一步测试 测定大鼠钠离子排泄量对钠通道的重要性 通道阻滞剂阿米洛利。其他运输通道的上调也将 使用噻嗪类药物阻断NaCI共转运蛋白和血管紧张素受体 拮抗剂以防止Na/H交换的上调。我们亦会评估 两条可能的信号通路在这些情况下对醛固酮分泌的作用 条件，肾素活性增加和血浆K升高。我们将探索 利德尔综合征的病理性上调机制 人类高血压。这将使用小鼠来完成，在小鼠中，通道亚单位 B-ENaC已被截断，以模仿人类的突变。在这里我们将测试 这种突变降低了之前基因下调的速度 激活的通道。最后，我们将研究胰岛素对心脏功能的影响。 频道。我们将检验这一假设，即这种荷尔蒙增加了 由醛固酮插入或激活的通道的概率。结果是 有助于理解通道介导的钠重吸收在不同环境下的作用 生理(饮食)压力和高血压的状况。

DESCRIPTION (provided by applicant): Epithelial Na channels are expressed in the distal parts of the mammalian nephron, and are known to be regulated by the renin-angiotensin-aldosterone axis. The role of these channels and their regulation by mineralocorticoids in the daily regulation of sodium excretion by the kidneys will be explored. Preliminary data indicate that when rats are given a low sodium diet, they can adjust their renal Na excretion within 15 hours and that increased reabsorption through Na channels can account for a large fraction of the reduced excretion rates. We will assess the role of the channels with different degrees of Na depletion, measuring both channel activity and overall urinary Na excretion. Channel activity will be measured as amiloride-sensitive whole-cell currents in the renal cortical collecting tubule as well as the medullary collecting duct and the connecting tubule to quantitate its contribution to renal Na handling. We will further test for the importance of Na channels by measuring Na excretion in rats treated with the channel blocker amiloride. Upregulation of other transport pathways will also be examined using thiazides to block NaCI cotransport and angiotensin receptor antagonists to prevent upregulation of Na/H exchange. We will also assess the roles of two putative signaling pathways for aldosterone secretion under these conditions, increased renin activity and elevated plasma K. We will explore the mechanisms of pathological upregulation seen in the Liddle's Syndrome form of human hypertension. This will be done using mice in which the channel subunit B-ENaC has been truncated to mimic the human mutation. Here we will test the idea that the mutation decreases the rate of downregulation of previously activated channels. Finally we will study the effects of insulin on the channels. We will examine the hypothesis that this hormone increases the open probability of channels inserted or activated by aldosterone. The results should help to understand the role of channel-mediated Na reabsorption under conditions of physiological (dietary) stress and hypertension.