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.

Public Health Relevance

The prevalence of overweight and obesity has dramatically increased during the past 2 decades with 65% of the United States adults being overweight and 31% of adult being obese. Obesity related hypertension is a major risk factor for cardiovascular diseases. The current proposal aims at understanding molecular mechanisms of obesity-induced hypertension. This proposal is expected to provide new information required for development of more effective therapies for the human disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Hypertension and Microcirculation Study Section (HM)
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Ketchum, Christian J
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University of Utah
Internal Medicine/Medicine
Schools of Medicine
Salt Lake City
United States
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