ROLE OF SENSING OF K+ INTAKE IN K+ HOMEOSTASIS

描述（由申请方提供）：细胞外（ECF）K+稳态对正常心血管和神经肌肉功能至关重要，并通过肾和肾外机制维持。我们最近开发了K钳技术，它可以定量在体内肾脏K+排泄和肾外细胞K+摄取。使用这种技术，我们证明了肾脏K+排泄和肾细胞外K+摄取在K+剥夺过程中迅速而深刻地受到抑制。传统上解释ECF K+保守性的这些变化是由于ECF K+水平降低和/或随之而来的醛固酮分泌减少。然而，我们发现，这种触发ECF K+的保护可以发生在大鼠血浆[K +]或[醛固酮]的变化时，K+摄入量减少到1/3的控制。本项目的目的是验证以下假设：K+摄入由门静脉中的K+传感器感知，肾脏K+排泄和肾外细胞K+摄取均受此信号调节。为了实现这一目标，我们将与我们机构的凯西多诺万博士合作，并采用与用于证明大鼠门静脉葡萄糖传感器存在的策略类似的策略，即，“局部灌注”和门静脉去神经技术。我们的初步数据显示，仅一晚（12小时）将K+摄入量减少至正常水平的1/3就足以触发显著的肾脏K+保护。在拟议的研究中，我们将使用这种夜间低K+喂养模型来解决以下具体目标。 目标1。检测是否存在Kv摄入的门静脉（或内脏）感知及其对肾和肾外K+处理的调节。我们将测试通过胃内或门静脉内输注的平行K+补充是否阻止了由隔夜低膳食K+摄入触发ECF K+保护，这将被假设的门静脉（或内脏）传感器感知，但不是通过全身输注的K+补充。 目标二。测试门静脉感知K+摄入在细胞外K+稳态中的作用。我们建议测试是否门静脉去神经消融门静脉感知的Kv摄入量，如果是这样，它是否损害急性和慢性调节ECF K+稳态延迟肾和肾外反应改变K+摄入量。 意义：该项目将潜在地确定一个重要的，以前未知的ECF K+稳态调节剂。

DESCRIPTION (provided by applicant): Extracellular (ECF) K+ homeostasis is critical for normal cardiovascular and neuromuscular functions and is maintained by renal and extrarenal mechanisms. We recently developed the K clamp technique, which can quantify both renal K+ excretion and extrarenal cellular K+ uptake in vivo. Using this technique, we demonstrated that both renal K+ excretion and extrarenal cellular K+ uptake are rapidly and profoundly suppressed during K+ deprivation. These changes for ECF K+ conservation have been traditionally explained to arise from decreased ECF K+ levels and/or consequent decrease in aldosterone secretion. However, we found that this triggering of ECF K+ conservation can occur in rats in the absence of changes in plasma [K +] or [aldosterone] when K+ intake is reduced to 1/3 of control. The objective of this project is to test the hypothesis that K+ intake is sensed by K+ sensors in the portal vein, and both renal K+ excretion and extrarenal cellular K+ uptake are regulated by this signal. To achieve this goal, we will collaborate with Dr. Casey Donovan at our institution and employ strategies similar to those used to demonstrate the presence of portal vein glucose sensors in rats, i.e., "local irrigation" and portal denervation techniques. Our preliminary data showed that reducing K+ intake to 1/3 of normal for only one night (12 h) was sufficient to trigger marked renal K+ conservation. In the proposed studies we will use this overnight low K+ feeding model to address the following specific aims. Aim 1. Test for the existence of portal (or splanchnic) sensing of Kv intake and its regulation of renal and extrarenal K+ handling. We will test whether the triggering of ECF K+ conservation by overnight low dietary K+ intake is prevented by parallel K+ supplementation via intragastric or intraportal infusion, which would be sensed by the hypothetical portal vein (or splanchnic) sensors, but not by K+ supplementation via systemic infusion. Aim 2. Test for a role of portal sensing of K+ intake in extracellular K+ homeostasis. We propose to test whether portal denervation ablates portal sensing of Kv intake and, if so, whether it impairs the acute and chronic regulation of ECF K+ homeostasis by delaying renal and extrarenal responses to altered K+ intake. Significance: This project will potentially identify an important, previously unknown regulator of ECF K+ homeostasis.