Interplay between Kir4.1/Kir5.1 channels, RAAS and electrolyte balance

摘要： 血压对盐摄入量的敏感性增强存在于近一半的美国人中， 高血压，包括约75%的非洲裔美国人高血压患者。钠的作用 血压取决于饮食成分，特别是Na+/K+比率。饮食补充高 K+与主要心血管事件的风险较低相关。尽管具有高度相关的临床和 翻译的证据支持高钾饮食的好处，有一个实质性的缺乏，在我们的 了解潜在的分子机制。醛固酮中的离子通道和转运蛋白- 敏感远端肾单位（ASDN）决定转运率和随后的尿排泄， 电解质，包括Na+和K+。抑制整流K+（Kir）通道，特别是Kir4.1/Kir5.1（编码为 Kcnj 10和Kcnj 16基因）是ASDN中主要的基底外侧K+通道， 在精确维持肾脏电解质稳态中的重要作用。我们之前的研究表明， 敲除Dahl盐敏感大鼠（SSKcnj 16-/-）中的Kcnj 16导致血压降低、盐消耗减少， 肾小管病变和低钾血症。此外，当喂食高盐饮食（HS; 4%NaCl）时， 恶化并导致SSKcnj 16-/-大鼠在几天内死亡。重要的是，膳食钾 补充以及用苯扎明处理抑制ENaC防止了盐诱导的死亡。然而，在这方面， 与SSKcnj 16-/-大鼠心肾异常相关的特定机制以及 Kir4.1/Kir5.1介导的钾离子转运与肾素-血管紧张素-醛固酮系统（RAAS，一种主要的 控制ASDN中液体和电解质平衡的激素系统）仍不清楚。除了SSKcnj 16-/- 我们已经建立了一个SSKcnj 10-/-模型，其中Kir4.1（Kcnj 10）也在SS大鼠中被敲除;这些 两个模型使我们能够评估Kir4.1/Kir5.1（Kcnj 10/Kcnj 16）通道在血压控制中的作用， 肾功能考虑到Kcnj 10/Kcnj 16与各种心肾疾病的相关性， 因此，了解Kir4.1/Kir5.1影响电解质的机制非常重要。 稳态，其他通道和转运蛋白的活性，以及盐背景下的血压控制- 诱发性高血压此外，Kir4.1/Kir5.1通道活动影响RAAS的能力， 高血压的主要控制者需要调查我推测Kir4.1/Kir5.1通道的活性 通过影响RAAS和电解质， 通过调节ASDN中的离子通道和转运蛋白来平衡。有两个具体目标， 提出的假设：1）确定肾Kir4.1/Kir5.1通道功能障碍对离子通道的影响， ASDN中的通道和全身电解质稳态; 2）确定 肾Kir4.1/Kir5.1通道和RAAS以及这种相互作用对血压控制的影响。

Abstract: Enhanced sensitivity of blood pressure to salt intake is present in nearly half of Americans afflicted with hypertension, including approximately 75% of African American hypertensive patients. The effect of sodium on blood pressure is dependent on diet composition, specifically on the Na+/K+ ratio. Diets supplemented with high K+ are associated with a lower risk of major cardiovascular events. Despite highly relevant clinical and translational evidence supporting the benefits of a high-potassium diet, there is a substantial lack in our understanding of the underlying molecular mechanisms. Ion channels and transporters in the aldosterone- sensitive distal nephron (ASDN) determine the transport rate and the subsequent urinary excretion of electrolytes, including Na+ and K+. Inwardly rectifying K+ (Kir) channels, specifically Kir4.1/Kir5.1 (encoded by Kcnj10 and Kcnj16 genes, respectively), are the major basolateral K+ channels in the ASDN and play an important role in precisely maintaining electrolyte homeostasis in the kidney. Our previous studies revealed that a knockout of Kcnj16 in the Dahl salt-sensitive rat (SSKcnj16-/-) results in decreased blood pressure, salt wasting tubulopathy, and hypokalemia. Furthermore, when fed a high salt diet (HS; 4% NaCl), hypokalemia was exacerbated and resulted in mortality of SSKcnj16-/- rats within a few days. Importantly, dietary potassium supplementation as well as ENaC inhibition with benzamil treatment prevented salt-induced death. However, specific mechanisms pertaining to the cardiorenal abnormalities in SSKcnj16-/- rats and the interaction of Kir4.1/Kir5.1-mediated potassium transport with the renin-angiotensin-aldosterone system (RAAS, a major hormone system that controls fluid and electrolyte balance in ASDN) remains unclear. In addition to SSKcnj16-/- rats, we have created an SSKcnj10-/- model in which Kir4.1 (Kcnj10) has also been knocked out in the SS rat; these two models enable us to assess the role of Kir4.1/Kir5.1 (Kcnj10/Kcnj16) channels in blood pressure control and renal function. Given the reported associations of Kcnj10/Kcnj16 with a variety of cardiorenal diseases in humans, 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 context of salt- induced hypertension. Additionally, the capacity of Kir4.1/Kir5.1 channel activity to influence the RAAS, another major controller of blood pressure, requires investigation. I hypothesize that the activity of Kir4.1/Kir5.1 channels in the distal nephron is a major determinant of blood pressure through influencing the RAAS as well as electrolyte balance by modulating ion channels and transporters in ASDN. There are two specific aims which will address the proposed hypothesis: 1) To determine the influence of dysfunctional renal Kir4.1/Kir5.1 channels on ion channels in the ASDN and on whole body electrolyte homeostasis; 2) To define the mechanistic link between renal Kir4.1/Kir5.1 channels and RAAS and the implications of this interaction for blood pressure control.