Epithelial Na Channels and Regulation of Na Excretion

描述（由申请人提供）：上皮Na通道在 哺乳动物肾单位的远端部分，并且已知由 肾素血管紧张素醛固酮轴这些渠道的作用及其 盐皮质激素对钠排泄的日常调节 肾脏将被探查。初步数据表明，当老鼠 给予低钠饮食，他们可以在15分钟内调整肾脏的钠排泄量， 小时，通过Na通道的重吸收增加可以解释 排泄率降低的大部分。我们将评估 具有不同程度Na耗尽的通道，测量两个通道 活性和总体尿钠排泄。通道活动将被测量为 肾皮质集合小管的阿米洛利敏感性全细胞电流 以及髓集合管和连接小管， 定量其对肾Na处理的贡献。我们将进一步测试 钠通道的重要性，通过测量钠排泄在大鼠治疗 通道阻断剂阿米洛利。其他转运途径的上调也将 使用噻嗪类药物阻断NaCl共转运和血管紧张素受体 拮抗剂以防止Na/H交换的上调。我们亦会评估 在这些条件下，两种假定的醛固酮分泌信号通路的作用 条件下，增加的肾素活性和升高的血浆K。我们将探讨 在Liddle综合征中观察到的病理性上调机制， 人类高血压这将使用小鼠来完成，其中通道亚基 B-ENaC已被截短以模拟人类突变。在这里，我们将测试 这种突变降低了先前基因表达下调的速率， 激活渠道最后，我们将研究胰岛素对 渠道我们将研究这种激素增加开放性的假设。 通道插入或激活醛固酮的概率。结果 应该有助于理解通道介导的钠重吸收的作用， 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.