Renal and extrarenal toxicity of aldosterone

醛固酮的肾毒性和肾外毒性

• 批准号: 9280815
• 负责人: David H Ellison
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9280815
• 关键词: Ablation; Adrenal Glands; Adverse effects; Agonist; Aldosterone; Angiotensin II; Animals; Binding; Blood Pressure; Cardiac; Cardiac Myocytes; Cardiotoxicity; Cardiovascular Diseases; Cardiovascular system; Carrier Proteins; Cells; Cessation of life; Chronic Kidney Failure; Clinical Research; Clinical Trials; DOCA; Data; Diet; Disease; Distal; Distal convoluted renal tubule structure; Duct (organ) structure; Electrolyte Balance; Enterobacteria phage P1 Cre recombinase; Epithelium; Excretory function; Extracellular Fluid; Fibrosis; Fludrocortisone; Fostering; Generations; Genetic; Glucocorticoids; Goals; Growth; Health; Heart; Heart failure; Hormones; Hyperaldosteronism; In Vitro; Individual; Kidney; Knockout Mice; Life; Lysine; Mediating; Methods; Mineralocorticoid Receptor; Mineralocorticoids; Modeling; Morbidity - disease rate; Movement; Mus; Nephrons; Organ; Pathologic; Patients; Perinatal; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Physiological; Play; Potassium; Prevention; Primary Hyperaldosteronism; Protein phosphatase; Proteins; Proteinuria; Renal tubule structure; Reporting; Role; SLC12A3 gene; Serum; Serum Proteins; Signal Pathway; Signal Transduction; Site; Sodium; Sodium Chloride; Testing; Text; Therapeutic; Tissues; Toxic effect; Toxin; Veterans; Zona Glomerulosa; cardiovascular disorder risk; clinically relevant; epithelial Na+ channel; experimental study; human disease; hyperkalemia; improved; in vivo; knockout animal; mortality; pressure; prevent; promoter; protein transport; public health relevance; receptor; response; wasting

DESCRIPTION (provided by applicant): Aldosterone is one of the most important cardiovascular toxins. Drugs aimed at blocking it prolong life in patients with heart failure, and reduce proteinuria in patients. Yet aldosterone is also an essential endogenous hormone, which has several important homeostatic functions. Drugs that block aldosterone actions, while useful, are also limited by side effects. These side effects are largely, although not exclusively, related to their actions on kidney tubules. Recently effects of aldosterone on kidney tubules have been suggested to be more widespread than previously believed, and involve the distal convoluted tubule, as well as the connecting tubule and collecting duct. Here, we will test for direct effects of aldosterone in mediating cardiac and renal damage by deleting mineralocorticoid receptors (MR) selectively from heart and kidney. Further, we will investigate the mechanisms by which aldosterone modulates the activity of the thiazide-sensitive Na-Cl cotransporter, along the distal convoluted tubule. Here, we will test the hypothesis that aldosterone effects along the distal convoluted tubule are essential for its renal actions, and that aldsosterone-induced renal damage depends on enhanced salt transport. We will also test how aldosterone signals to the thiazide-sensitive Na-Cl cotransporter through SGK1. In Aim #2, we will examine role of cardiac MR in mediating cardiac damage in the face of hyperaldosteronism. We will use animals in which MR is flanked by LoxP sites. When these animals are bred with animals expressing CRE recombinase, under the control of a tissue specific promoter, it permits MR to be deleted. We have obtained animals in which CRE recombinase is under the control of inducible promoters specific for cardiac myocytes and kidney tubules and have bred inducible knockout animals. For the cardiac experiments, animals will undergo uninephrectomy followed by deletion of cardiac MR. They will then consume fludrocortisone and the effects of cardiac myocyte MR deletion on cardiac toxicity will be determined. For the renal MR deletion experiments, the tubule MR will be deleted first along the entire nephron and then in the distal convoluted tubule specifically. The animal phenotypes will then be determined during normal conditions and after the generation of kidney damage. For the experiments testing mechanisms of MR action on distal salt transport, effects of the aldosterone-induced protein SGK1 on the WNK/SPAK signaling pathway will be examined in cells and in vitro. This project is clinically relevant, as aldosterone contributes importantly to cardiovascular death. Blocking it is important therapeutically, but is hazardous, owing to renal toxicity. If we can demonstrate that cardiac MR is essential for destructive effects of aldosterone, treatment can be directed at blockade in the heart, while avoiding blockade in the kidney. In the kidney, if we can demonstrate that aldosterone effects independent of blood pressure are essential for renal protection, then glomerulus specific MR modulators can be developed. Furthermore, cardiovascular disease is the number one killer of veterans. Blocking MR is considered essential for its prevention. Better and safer methods to achieve this will enhance the health of veterans.

描述（由申请人提供）： 醛固酮是最重要的心血管毒素之一。旨在阻断它的药物可以延长心力衰竭患者的生命，并减少患者的蛋白尿。然而，醛固酮是 也是一种必需的内源性激素，具有几种重要的稳态功能。阻断醛固酮作用的药物虽然有用，但也受到副作用的限制。这些副作用在很大程度上（尽管不是唯一的）与它们对肾小管的作用有关。最近，醛固酮对肾小管的作用比以前认为的更广泛，并且涉及远曲小管以及连接小管和集合管。在这里，我们将测试醛固酮介导的心脏和肾脏损伤的直接影响，通过删除盐皮质激素受体（MR）选择性从心脏和肾脏。此外，我们还将研究醛固酮调节沿着远曲小管噻嗪敏感性钠-氯协同转运蛋白活性的机制。在这里，我们将测试的假设，即醛固酮的影响沿着远曲小管是必不可少的，其肾脏的行动，以及醛固酮诱导的肾损害取决于盐转运增强。我们还将测试醛固酮如何通过SGK 1向噻嗪敏感性Na-Cl协同转运蛋白发出信号。在目标2中，我们将研究心脏MR在介导醛固酮增多症心脏损伤中的作用。我们将使用MR两侧为LoxP位点的动物。当这些动物与表达CRE重组酶的动物在组织特异性启动子的控制下繁殖时，它允许MR被删除。我们已经获得了CRE重组酶在心肌细胞和肾小管特异性诱导型启动子控制下的动物，并培育了诱导型敲除动物。对于心脏实验，动物将接受单肾切除术，然后删除心脏MR。然后，它们将消耗氟氢可的松，并确定心肌细胞MR删除对心脏毒性的影响。对于肾MR删除实验，首先沿着整个肾单位删除小管MR，然后在远曲小管中特异性地删除。然后将在正常条件下和产生肾损伤后确定动物表型。对于测试MR作用于远端盐转运的机制的实验，将在细胞和体外检查醛固酮诱导的蛋白SGK 1对WNK/SPAK信号传导途径的影响。该项目具有临床意义，因为醛固酮对心血管死亡有重要作用。阻断它在治疗上是重要的，但由于肾毒性，是危险的。如果我们能够证明心脏MR对于醛固酮的破坏性作用是必不可少的，那么治疗可以针对心脏的阻断，同时避免肾脏的阻断。在肾脏，如果我们能证明醛固酮的作用独立于血压是必不可少的肾脏保护，那么肾小球特异性MR调节剂可以开发。此外，心血管疾病是退伍军人的头号杀手。阻断MR被认为是预防MR的关键。更好和更安全的方法来实现这一目标将提高退伍军人的健康。