Na+-sensitive elevation in blood pressure is ENaC independent in diet-induced obesity and insulin resistance

Author:

Nizar Jonathan M.1,Dong Wuxing1,McClellan Robert B.1,Labarca Mariana1,Zhou Yuehan2,Wong Jared1,Goens Donald G.1,Zhao Mingming3,Velarde Nona1,Bernstein Daniel3,Pellizzon Michael4,Satlin Lisa M.2,Bhalla Vivek1

Affiliation:

1. Division of Nephrology, Department of Medicine, Stanford University, Palo Alto, California;

2. Division of Pediatric Nephrology, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York;

3. Division of Pediatric Cardiology, Department of Pediatrics, Stanford University, Stanford, California; and

4. Research Diets, Incorporated, New Brunswick, New Jersey

Abstract

The majority of patients with obesity, insulin resistance, and metabolic syndrome have hypertension, but the mechanisms of hypertension are poorly understood. In these patients, impaired sodium excretion is critical for the genesis of Na+-sensitive hypertension, and prior studies have proposed a role for the epithelial Na+ channel (ENaC) in this syndrome. We characterized high fat-fed mice as a model in which to study the contribution of ENaC-mediated Na+ reabsorption in obesity and insulin resistance. High fat-fed mice demonstrated impaired Na+ excretion and elevated blood pressure, which was significantly higher on a high-Na+ diet compared with low fat-fed control mice. However, high fat-fed mice had no increase in ENaC activity as measured by Na+ transport across microperfused cortical collecting ducts, electrolyte excretion, or blood pressure. In addition, we found no difference in endogenous urinary aldosterone excretion between groups on a normal or high-Na+ diet. High fat-fed mice provide a model of metabolic syndrome, recapitulating obesity, insulin resistance, impaired natriuresis, and a Na+-sensitive elevation in blood pressure. Surprisingly, in contrast to previous studies, our data demonstrate that high fat feeding of mice impairs natriuresis and produces elevated blood pressure that is independent of ENaC activity and likely caused by increased Na+ reabsorption upstream of the aldosterone-sensitive distal nephron.

Funder

HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

American Society of Nephrology (ASN)

Stanford University School of Medicine (Stanford School of Medicine, Stanford Medicine, Stanford University)

American Heart Association (AHA)

Publisher

American Physiological Society

Subject

Physiology

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