Role of basolateral K channels in renal salt handling and BP control

血压对盐摄入量的敏感度增加的美国人中，有近一半的人受到 高血压，包括大约75%的非裔美国人高血压患者。底侧向内 纠正K+(KIR)通道，特别是Kir4.1和Kir4.1/Kir5.1(由Kcnj10和Kcnj16基因编码)发挥作用 在调节对醛固酮敏感的远端肾单位的水和电解质运输中起主导作用。肾 KIR4.1/Kir5.1异构体是位于远端和集合管的主细胞和集合管的主要基底外侧通道。 在调节血浆K+水平和Na+重吸收中起重要作用。这条通道的故障 由遗传或药物相关因素引起的可直接参与低血钾、高钾和 人类的高血压病理。另一方面，精确的药物或基因调控 Kir4.1或Kir5.1亚基可能为控制体内电解质平衡提供新的有用工具，并将 开辟治疗和预防盐敏性高血压和肾脏损害的新方法。这个 Dahl盐敏感型(SS)大鼠是一种自然发生的盐敏性高血压模型，它概括了许多 进行性人类疾病的各个方面为盐敏感的潜在机制提供了关键的见解。我们 建立了SS大鼠(SSKcnj10-/-和SSKcnj16-)Kir4.1或Kir5.1基因缺失的两种大鼠模型。 /-大鼠)，使我们能够评估Kir4.1和Kir4.1/Kir5.1通道在K+控制中的作用 动态平衡与盐敏感型高血压的发展。鉴于已报道的Kir4.1/Kir5.1的关联 对于各种心肾疾病，了解Kir4.1/Kir5.1通过何种机制可以 对电解质稳态、其他通道和转运体活性及血压控制的影响 盐性高血压的发病环境。这项建议的具体目标是1)定义动态相互作用 肾脏中Kir4.1/Kir5.1、NCC、ENaC通道/转运体和RAAS之间的关系及其作用 体内电解质平衡的控制机制。高盐和低盐胁迫下RAAS激素的变化 饲料钾补充剂，DCT和CCD管单个细胞的基侧膜电位， NCC和ENaC活性、钠/钾稳态及一种盐皮质激素受体抑制剂的作用 将在SSKcnj10-/-和SSKcnj16-/-大鼠身上进行测试。2)确定Kir4.1/Kir5.1的药理抑制作用 减轻盐引起的高血压。我们的初步和已发表的实验表明，去甲替林和 FDA批准的第二代三环类抗抑郁药，显著降低Kir4.1/Kir5.1介导的K+- 选择性电导和调节细胞内的ENaC活性。使用新的特定化合物，如 VU992、VU690和VU726在WT和SSKcnj16-/-大鼠体内，我们将确定Kir4.1/Kir5.1作为一种 调节体内钠钾动态平衡的药理靶点。我们假设直接 基底外侧KIR通道活性的调节将在盐诱导的发育中起保护作用 并将导致发现更有效的治疗高血压的方法。

Enhanced sensitivity of blood pressure to salt intake is present in nearly half of Americans affected by hypertension, including approximately 75% of African American hypertensive patients. Basolateral inwardly rectifying K+ (Kir) channels, specifically Kir4.1 and Kir4.1/Kir5.1 (encoded by Kcnj10 and Kcnj16 genes), play a dominant role in modulating water and electrolyte transport in the aldosterone-sensitive distal nephron. Renal Kir4.1/Kir5.1 heterotetramer is a primary basolateral channel at the distal and collecting ducts principal cells and plays an essential role in the regulation of plasma K+ level and Na+ reabsorption. The malfunction of this channel caused by genetic or medication-related factors can be directly involved in hypokalemic, hyperkalemic and hypertensive pathologies in humans. From the other side, precise pharmacological or genetic modulation of Kir4.1or Kir5.1 subunits may provide a new useful tool to the control of electrolyte balance in the body and will open new ways to treat and prevent the development of salt-sensitive hypertension and kidney damage. The Dahl Salt-Sensitive (SS) rat, a naturally occurring model of salt-sensitive hypertension, recapitulates many aspects of progressive human disease providing key insights into mechanisms underlying salt-sensitivity. We have created two rat models in which Kir4.1or Kir5.1 have been knocked out in the SS rat (SSKcnj10-/- and SSKcnj16- /- rats, respectively), enabling us to assess the role of both Kir4.1and Kir4.1/Kir5.1 channels in the control of K+ homeostasis and the development of salt-sensitive hypertension. Given the reported associations of Kir4.1/Kir5.1 with a variety of cardiorenal diseases, it is important to understand the mechanisms by which Kir4.1/Kir5.1 can influence electrolyte homeostasis, the activity of other channels and transporters, and blood pressure control in the setting of salt-induced hypertension. The Specific Aims of this proposal are 1) To define the dynamic interplay between Kir4.1/Kir5.1, NCC, ENaC channels/transporters and RAAS in the kidney and the role of these mechanisms in the control of electrolyte balance in the body. Changes in RAAS hormones under high salt and dietary potassium supplements, basolateral membrane potential in individual cells of DCT and CCD tubules, NCC and ENaC activity, sodium/potassium homeostasis, and the effect of a mineralocorticoid receptor inhibitors will be tested in SSKcnj10-/- and SSKcnj16-/- rats. 2) To determine if pharmacological inhibition of Kir4.1/Kir5.1 attenuates salt-induced hypertension. Our preliminary and published experiments revealed that nortriptyline, an FDA-approved second-generation tricyclic antidepressant, significantly decreases Kir4.1/Kir5.1-mediated K+- selective conductance and modulates ENaC activity in CCD cells. Using novel specific compounds, such as VU992, VU690, and VU726 in WT and SSKcnj16-/- rats, we will determine the viability of Kir4.1/Kir5.1 as a pharmacological target to regulate sodium-potassium homeostasis in the body. We hypothesize that direct modulation of basolateral Kir channel activity will play a protective role in the development of salt-induced hypertension and will lead to the discovery of more effective treatments for high blood pressure.