Role of ANGII in mediating K secretion with a high K diet

ANGII 在高钾饮食介导钾分泌中的作用

• 批准号: 10248226
• 负责人: STEVEN SANSOM
• 金额: $ 9.91万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10248226
• 关键词: Address; Adrenergic alpha-Antagonists; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Angiotensins; Bartter Disease; Chronic; Chronic Kidney Failure; Consumption; Creatinine; Creatinine clearance measurement; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Dangerousness; Data; Diet; Distal; Equilibrium; Excretory function; Exhibits; Fatigue; Hydronephrosis; Hypertension; Hypertrophy; KCNJ1 gene; Kidney; Kidney Failure; Knock-out; Knockout Mice; Lead; Literature; Liver; Mediating; Metabolic; Micropuncture; Modeling; Mus; Na(+)-K(+)-Exchanging ATPase; Natriuresis; Nephrons; Output; Pathway interactions; Patients; Pharmaceutical Preparations; Plasma; Potassium; Potassium Channel; Process; Rattus; Renal Mass; Renal function; Renin; Role; Signal Pathway; Signal Transduction; Sudden Death; System; Therapeutic; Tissues; base; blood pressure reduction; cyclic GMP-binding protein; design; epithelial Na+ channel; guanylin; hyperkalemia; inhibitor/antagonist; kidney cell; mouse model; patch clamp; prevent; receptor; response; saluretic; urinary

Project Summary Angiotensin converting enzyme (ACE) inhibitors are regularly given to patients during early stages of chronic kidney disease (CKD). However, the benefits of slowing the progression of CKD are often overshadowed by dangerous episodes of hyperkalemia. In moderate CKD (stage 3; MCKD), the surviving nephrons adapt to high K diets with an extremely enhanced rate of K secretion per nephron. These proposed studies are designed to determine the importance of angiotensin II and why ACE inhibitors have such dangerous hyperkalemic effects in renal failure beginning in stage 3. This information should provide alternative therapeutic choices designed to prevent hypertension and hyperkalemia with high K consumption in moderate stages of renal failure. Aldosterone responds to chronically elevated plasma [K] and enhances expression of the epithelial Na channel (ENaC) and the Na-K-ATPase in the distal nephron. However, it is just as important to maintain a high rate of Na delivery to ENaC and the Na-K-ATPase. It has been known for decades that a high K diet (HK) causes a large natriuretic response. However, the signaling pathway is not understood. Based on our preliminary results and the literature, we hypothesize that a high K diet stimulates urinary ANGII, which activates AT2 receptors, thereby reducing Na reabsorption in the proximal tubule and increasing Na delivery to stimulate K secretion from K channels in the distal nephron. Aim #1 will determine whether liver- or PT-generated ANGII enhances K excretion in normal mice on HK and the 5/6 nephrectomized mouse model of renal failure. For this Aim, we will employ liver only angiotensinogen knockout mice (LKO) and double liver plus PT angiotensinogen knockout mice (DKO). Our preliminary results show that urinary ANGII is elevated by 5 to 8 fold in WT and LKO mice on HK (5%) but is not elevated in DKO on HK. When placed on HK, DKO, but not WT or LKO, exhibit severe hyperkalemia and a reduced urinary [K]/[creatinine]. We also find that PD123319, a blocker of ANGII 2 receptors (AT2), reduce HKIN in WT mice. For Aim #2, we will determine whether the AT2 receptor-cGMP-kinase pathway causes HKIN by inhibiting the Na-H exchanger 3 (NHE3) in the PT. Mice with a knock-out of the renal outer medullary K channel (ROMK-KO) are a model of Bartters syndrome but also are absent ROMK-mediated K secretion. ROMK-KO exhibit MCKD with GFR of approximately 55% of WT. Despite the compromised GFR and lack of ROMK-mediated K secretion, ROMK-KO maintain K balance on HK. Our preliminary results indicate that ROMK-KO compensate for the lack ROMK with enhanced HKIN that presumably stimulates large, Ca-activated K channels (BK). The enhanced HKIN may result from our finding of increased renal guanylin expression in ROMK-KO on HK. For Aim 3, we will explore whether enhanced guanylin-cGMP signaling of HK fed ROMK-KO inhibits Na reabsorption in the PT and increases Na delivery to stimulate K secretion via BK.

项目摘要 血管紧张素转换酶（ACE）抑制剂定期给予患者在早期阶段的慢性 肾病（CKD）。然而，减缓CKD进展的益处往往被以下因素所掩盖： 高钾血症的危险发作。在中度CKD（3期; MCKD）中，存活的肾单位适应高血压， 含钾饮食，每个肾单位的钾分泌率极高。这些拟议的研究旨在 确定血管紧张素II的重要性，以及为什么ACE抑制剂具有如此危险的高钾血症作用 肾功能衰竭从第三阶段开始这些信息应提供替代治疗选择， 预防高血压和高钾血症以及中度肾衰竭时的高钾消耗。醛固酮 响应慢性升高的血浆[K]，并增强上皮Na通道（ENaC）的表达， 远端肾单位的Na-K-ATP酶。然而，维持高的Na输送速率， ENaC和Na-K-ATP酶。几十年来，人们已经知道高钾饮食（HK）会导致大量利钠尿， 反应然而，信号传导途径尚不清楚。根据我们的初步结果和文献， 我们假设高钾饮食刺激尿ANGII，从而激活AT 2受体， 减少近端小管中的Na重吸收并增加Na递送以刺激K分泌， 远端肾单位的钾通道。目的#1将确定肝脏或PT产生的ANGII是否增强K 在HK和肾衰竭的5/6肾切除小鼠模型上的正常小鼠中的排泄。为此，我们将 使用仅肝脏血管紧张素原敲除小鼠（LKO）和双肝脏加PT血管紧张素原敲除小鼠 小鼠（DKO）。我们的初步结果表明，在WT和LKO小鼠中，尿ANGII升高5至8倍， HK（5%），但在HK的DKO中未升高。当放置在HK上时，DKO，而不是WT或LKO，表现出严重的 高钾血症和尿[K]/[肌酐]降低。我们还发现，PD 123319，一个血管紧张素Ⅱ 2受体的阻断剂， (AT2)降低WT小鼠的HKIN。对于目标#2，我们将确定AT 2受体-cGMP-激酶通路是否 通过抑制PT中的Na-H交换剂3（NHE 3）引起HKIN。敲除肾脏外膜蛋白基因的小鼠 延髓K通道（ROMK-KO）是Bartters综合征的模型，但也缺乏ROMK介导的K通道。 分泌物。ROMK-KO表现出MCKD，GFR约为WT的55%。尽管GFR受损， 由于ROMK介导K分泌不足，ROMK-KO维持HK上的K平衡。我们的初步结果表明， ROMK-KO用增强的HKIN弥补了ROMK的缺乏，这可能刺激了大的Ca激活的 K通道（BK）。增强的HKIN可能是由于我们发现肾脏鸟苷素表达增加， ROMK-KO在香港。对于目标3，我们将探索是否增强HK喂食ROMK-KO的鸟苷肽-cGMP信号传导 抑制PT中的Na重吸收并增加Na递送以刺激通过BK的K分泌。