title: Na+-sensitive elevation in blood pressure is ENaC independent in diet-induced obesity and insulin resistance.
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.
authors: Division of Nephrology, Department of Medicine, Stanford University, Palo Alto, California;
authors: Jonathan M
authors: JM
authors: Nizar
authors: Division of Nephrology, Department of Medicine, Stanford University, Palo Alto, California;
authors: Wuxing
authors: W
authors: Dong
authors: Division of Nephrology, Department of Medicine, Stanford University, Palo Alto, California;
authors: Robert B
authors: RB
authors: McClellan
authors: Division of Nephrology, Department of Medicine, Stanford University, Palo Alto, California;
authors: Mariana
authors: M
authors: Labarca
authors: Division of Pediatric Nephrology, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York;
authors: Yuehan
authors: Y
authors: Zhou
authors: Division of Nephrology, Department of Medicine, Stanford University, Palo Alto, California;
authors: Jared
authors: J
authors: Wong
authors: Division of Nephrology, Department of Medicine, Stanford University, Palo Alto, California;
authors: Donald G
authors: DG
authors: Goens
authors: Division of Pediatric Cardiology, Department of Pediatrics, Stanford University, Stanford, California; and.
authors: Mingming
authors: M
authors: Zhao
authors: Division of Nephrology, Department of Medicine, Stanford University, Palo Alto, California;
authors: Nona
authors: N
authors: Velarde
authors: Division of Pediatric Cardiology, Department of Pediatrics, Stanford University, Stanford, California; and.
authors: Daniel
authors: D
authors: Bernstein
authors: Research Diets, Incorporated, New Brunswick, New Jersey.
authors: Michael
authors: M
authors: Pellizzon
authors: Division of Pediatric Nephrology, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York;
authors: Lisa M
authors: LM
authors: Satlin
authors: Division of Nephrology, Department of Medicine, Stanford University, Palo Alto, California; vbhalla@stanford.edu.
authors: Vivek
authors: V
authors: Bhalla
mesh_terms: D000450:Aldosterone / Q000652:urine; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002940:Circadian Rhythm; D059305:Diet, High-Fat; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D007333:Insulin Resistance; D007685:Kidney Tubules, Collecting / Q000187:drug effects / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009318:Natriuresis; D009399:Nephrons / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000378:metabolism*; D012964:Sodium / Q000494:pharmacology* / Q000652:urine; D012982:Sodium, Dietary / Q000009:adverse effects
chemical_list: D053503:Epithelial Sodium Channels; D012982:Sodium, Dietary; D000450:Aldosterone; D012964:Sodium
keywords: epithelial sodium channel; insulin resistance; metabolic syndrome; obesity; sodium homeostasis