Control of collecting duct function by lipid-derived factors in obesity

肥胖中脂质衍生因子对集合管功能的控制

• 批准号: 8504453
• 负责人: Tianxin Yang
• 金额: $ 30.28万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8504453
• 关键词: 9-deoxy-delta-9-prostaglandin D2; Accounting; Adult; Affect; African American; Aldosterone; Animals; Antihypertensive Agents; Arachidonic Acids; Blood Pressure; Body Weight; Cardiovascular Diseases; Cells; Clinical; Consensus; Development; Diet; Dinoprostone; Distal; Duct (organ) structure; Effectiveness; Equilibrium; Essential Hypertension; Excretory function; Exhibits; Fasting; Fatty acid glycerol esters; Feedback; Hormones; Hypertension; Infusion procedures; Ion Transport; Kidney; Kidney Transplantation; Ligands; Lipids; Liquid substance; Mediating; Metabolic stress; Metabolic syndrome; Metabolism; Molecular; Molecular Target; Mus; Natriuresis; Nephrons; Obesity; Obesity Related Hypertension; Overweight; PPAR Pathway; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Phenotype; Play; Prevalence; Production; Prostaglandin D2; Prostaglandin H2; Randomized Clinical Trials; Resistance; Risk; Risk Factors; Role; Sodium; Sodium Chloride; Source; Syndrome; Testing; United States; base; blood pressure regulation; effective therapy; epithelial Na+ channel; gain of function mutation; human disease; improved; insight; mouse model; novel; prostaglandin E synthase-1; public health relevance; response; salt sensitive; saluretic; urinary

DESCRIPTION (provided by applicant): Obesity is often accompanied by significantly elevated blood pressure (BP), accounting for as much as 65-75% of the risk for essential hypertension. Obesity-induced hypertension is often resistant to conventional antihypertensive therapies, similar to Little syndrome which is caused by gain-of- function mutation of ENaC. Despite a strong association between body weight and BP, the etiologic basis of obesity-induced hypertension is unclear. There is a consensus, however, that increased Na+ reabsorption by the kidney may play a major role. Emerging evidence from clinical and animal studies further suggests that Na retention in obesity may occur primarily through overactivation of ENaC in the distal nephron. In particular, a randomized clinical trial demonstrated effectiveness of ENaC inhibition for improving BP control in black Americans (all of whom were clinically obese). In the present application, we propose to test the hypothesis that obesity-induced hypertension is caused by an imbalance of sodium regulatory hormones in the collecting duct (CD) with overactivation of natriferic prostaglandin D2 (PGD2)/15-deoxy-delta(12,14)-PGJ2 (15d- PGJ2)/PPAR pathway and suppression of natriuretic microsomal prostaglandin E synthase-1 (mPGES-1)/PGE2 pathway. Major approaches proposed in this application involve analysis of the phenotype of newly generated mice with CD-specific deletion of mPGES-1. We will further employ molecular and electrophysiological approaches to determine ENaC as the molecular target of PGE2 and WNK4-mediated paracellular transport as the molecular target of PPAR. The new information resulted from this proposal is expected to provide novel insight into dysregulation of fluid metabolism in metabolic syndrome.

描述（由申请人提供）：肥胖通常伴随着血压显着升高（BP），占基本高血压风险的65-75％。肥胖引起的高血压通常对常规降压疗法具有抵抗力，类似于少量综合征，这是由于ENAC的功能突变引起的。尽管体重与BP之间有很强的关联，但肥胖引起的高血压的病因基础尚不清楚。然而，达成共识，肾脏可以提高Na+的重吸收，可能发挥重要作用。来自临床和动物研究的新兴证据进一步表明，肥胖症中的NA保留可能主要是通过远端肾脏中的ENAC过度激活。特别是，一项随机临床试验表明，ENAC抑制对改善黑人美国人的BP控制的有效性（所有这些人都是临床肥胖的）。在本应用中，我们提议测试以下假设：肥胖性诱发的高血压是由钠调节激素在收集导管中的失衡而引起的，而纳地那二酸前列腺素D2（pgd2222）/15-deoxy-delta（12,14）-pgj2 and pparj2（15d-ppar）antriferic Prostaglandin D2（PGD2）/15d-ppary and Parriferic Prostaglandin D2（PGD2）（PGD2）（15d-ppar）引起的假设。微粒体前列腺素E合酶1（MPGES-1）/PGE2途径。在此应用中提出的主要方法涉及对MPGES-1的CD特异性缺失的新生成小鼠的表型的分析。我们将进一步采用分子和电生理方法来确定ENAC为PGE2和WNK4介导的细胞流传输的分子靶标作为PPAR的分子靶标。预计该提案产生的新信息将提供有关代谢综合征流体代谢失调的新洞察力。