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.

项目概要 慢性疾病早期阶段的患者定期服用血管紧张素转换酶 (ACE) 抑制剂。 肾脏疾病（CKD）。然而，减缓 CKD 进展的益处常常被以下因素所掩盖： 高钾血症的危险发作。在中度 CKD（第 3 阶段；MCKD）中，幸存的肾单位适应高 每个肾单位的钾分泌率极大提高的钾饮食。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作用 在第 3 阶段开始的肾功能衰竭中。此信息应提供替代治疗选择，旨在 肾功能衰竭中度阶段高钾消耗可预防高血压和高钾血症。醛固酮 对长期升高的血浆 [K] 做出反应并增强上皮 Na 通道 (ENaC) 的表达和 远端肾单位的 Na-K-ATP 酶。然而，保持 Na 的高输送率同样重要。 ENaC 和 Na-K-ATP 酶。几十年来，人们都知道高钾饮食 (HK) 会导致大量钠尿 回复。然而，信号通路尚不清楚。根据我们的初步结果和文献， 我们假设高 K 饮食会刺激尿 ANGII，从而激活 AT2 受体，从而 减少近曲小管的钠重吸收，增加钠的输送，刺激钾的分泌 K 通道位于远端肾单位。目标 #1 将确定肝脏或 PT 生成的 ANGII 是否增强 K HK 正常小鼠和肾衰竭 5/6 肾切除小鼠模型中的排泄。为了这个目标，我们将 采用仅肝脏血管紧张素原基因敲除小鼠 (LKO) 和双肝加 PT 血管紧张素原基因敲除小鼠 小鼠（DKO）。我们的初步结果表明，WT 和 LKO 小鼠的尿液 ANGII 升高了 5 至 8 倍。 HK (5%) 但在 HK 上的 DKO 中并未升高。当放置在 HK、DKO（但不是 WT 或 LKO）上时，表现出严重的 高钾血症和尿 [K]/[肌酐] 降低。我们还发现 PD123319，ANGII 2 受体阻断剂 (AT2)，减少 WT 小鼠的 HKIN。对于目标#2，我们将确定 AT2 受体-cGMP-激酶通路是否 通过抑制 PT 中的 Na-H 交换器 3 (NHE3) 引起 HKIN。肾外膜敲除的小鼠 髓质 K 通道 (ROMK-KO) 是 Bartters 综合征的模型，但不存在 ROMK 介导的 K 通道 分泌。 ROMK-KO 表现出 MCKD，GFR 约为 WT 的 55%。尽管肾小球滤过率（GFR）受损 缺乏ROMK介导的钾分泌，ROMK-KO维持HK上的钾平衡。我们的初步结果表明 ROMK-KO 通过增强的 HKIN 来补偿 ROMK 的缺乏，HKIN 可能会刺激大的、Ca 激活的 K 通道 (BK)。 HKIN 增强可能是由于我们发现肾鸟苷蛋白表达增加所致 ROMK-KO 在香港。对于目标 3，我们将探讨 HK 喂养的 ROMK-KO 是否增强鸟苷酸-cGMP 信号传导 抑制 PT 中 Na 的重吸收，并增加 Na 输送，通过 BK 刺激 K 分泌。