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

描述（由申请人提供）：肥胖通常伴有血压（BP）显著升高，占原发性高血压风险的65-75%。肥胖性高血压对传统的降压治疗往往具有抵抗性，类似于由ENaC功能获得性突变引起的Little综合征。尽管体重和血压之间有很强的相关性，但肥胖性高血压的病因学基础尚不清楚。然而，有一个共识，即肾脏对Na+重吸收的增加可能起主要作用。来自临床和动物研究的新证据进一步表明，肥胖症中的Na潴留可能主要通过远端肾单位中ENaC的过度激活而发生。特别是，一项随机临床试验证明了ENaC抑制对改善美国黑人（所有人都是临床肥胖）的血压控制的有效性。在本申请中，我们提出检验肥胖诱导的高血压是由集合管（CD）中钠调节激素的失衡引起的，其中钠化前列腺素D2（PGD 2）/15-脱氧-δ（12，14）-PGJ 2（15 d-PGJ 2）/PPAR途径过度活化，以及利钠微粒体前列腺素E合酶-1（mPGES-1）/PGE 2途径受到抑制。本申请中提出的主要方法涉及分析具有mPGES-1的CD特异性缺失的新产生小鼠的表型。我们将进一步采用分子和电生理学方法来确定ENaC作为PGE 2的分子靶点和WNK 4介导的细胞旁转运作为PPAR的分子靶点。这一新的研究结果有望为代谢综合征中液体代谢异常的研究提供新的思路。

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.