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

描述（由申请人提供）：肥胖常伴有血压显著升高，占原发性高血压风险的65-75%。肥胖引起的高血压通常对常规降压治疗具有抗性，类似于ENaC基因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联系，但肥胖引起的高血压的病因学基础尚不清楚。然而，有一个共识是，肾脏增加的Na+重吸收可能起主要作用。来自临床和动物研究的新证据进一步表明，肥胖中的钠潴留可能主要是通过远端肾单位ENaC的过度激活发生的。特别是，一项随机临床试验证明了ENaC抑制对改善美国黑人血压控制的有效性（他们均为临床肥胖）。在本应用中，我们提出验证肥胖引起的高血压是由集管（CD）钠调节激素失衡引起的，钠性前列腺素D2 (PGD2)/15-deoxy-delta(12,14)-PGJ2 (15d- PGJ2)/PPAR通路过度激活和钠性微粒体前列腺素E合成酶-1 (mpgs -1)/PGE2通路抑制。在这一应用中提出的主要方法包括分析cd特异性缺失mPGES-1的新生小鼠的表型。我们将进一步采用分子和电生理学方法确定ENaC是PGE2的分子靶点，wnk4介导的细胞旁转运是PPAR的分子靶点。这一建议的新信息有望为代谢综合征中液体代谢失调提供新的见解。

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.