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Author Notes:

Address correspondence to: Jens Titze, Division of Clinical Pharmacology, Vanderbilt University Medical Center, 2213 Garland Avenue, P435F MRBIV, Nashville, Tennessee 37232, USA. Phone: 615.343.1401; E-mail: jens.m.titze@vanderbilt.edu.

See publication for full list of author contributions.

We thank N. Mizushima (University of Tokyo) for providing GFP-LC3#53 mice.

We are grateful to the excellent technical assistance of Yan Zhao (Vanderbilt University Medical Center, Nashville, TN, USA), Jenny Hähnel, and Ulrike Goller (University Clinic Erlangen, Erlangen, Germany).

The authors have declared that no conflict of interest exists.

Subjects:

Research Funding:

This work was supported by grants from the NIH (RO1 HL118579-01, to JT; R01-DK41707 and R01-DK89828, to JS; and U24 DK059637, to DHW); the American Heart Association (AHA) (14SFRN20770008); the German Federal Ministry for Economics and Technology/DLR Forschung unter Weltraumbedingungen (50WB1624, to JT); the Deutsche Forschungsgemeinschaft (DFG) (SFB 643 B16, to JT and JJ; DA 1835/1-1, to SD); the TOYOBO Biotechnology Foundation (to KK); and the Interdisciplinary Center for Clinical Research Erlangen (to JT).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Medicine, Research & Experimental
  • Research & Experimental Medicine
  • ACTIVATED PROTEIN-KINASE
  • ACETYL-COA CARBOXYLASE
  • AMINO-ACID-METABOLISM
  • AFRICAN LUNGFISH
  • UREA TRANSPORTER
  • IN-VIVO
  • PROTOPTERUS-AETHIOPICUS
  • PROLONGED STARVATION
  • RAT MUSCLE
  • ESTIVATION
  • Metabolism
  • Nephrology

High salt intake reprioritizes osmolyte and energy metabolism for body fluid conservation

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Journal Title:

Journal of Clinical Investigation

Volume:

Volume 127, Number 5

Publisher:

, Pages 1944-1959

Type of Work:

Article | Final Publisher PDF

Abstract:

Natriuretic regulation of extracellular fluid volume homeostasis includes suppression of the renin-angiotensin-aldosterone system, pressure natriuresis, and reduced renal nerve activity, actions that concomitantly increase urinary Na+ excretion and lead to increased urine volume. The resulting natriuresis-driven diuretic water loss is assumed to control the extracellular volume. Here, we have demonstrated that urine concentration, and therefore regulation of water conservation, is an important control system for urine formation and extracellular volume homeostasis in mice and humans across various levels of salt intake. We observed that the renal concentration mechanism couples natriuresis with correspondent renal water reabsorption, limits natriuretic osmotic diuresis, and results in concurrent extracellular volume conservation and concentration of salt excreted into urine. This water-conserving mechanism of dietary salt excretion relies on urea transporter-driven urea recycling by the kidneys and on urea production by liver and skeletal muscle. The energy-intense nature of hepatic and extrahepatic urea osmolyte production for renal water conservation requires reprioritization of energy and substrate metabolism in liver and skeletal muscle, resulting in hepatic ketogenesis and glucocorticoid-driven muscle catabolism, which are prevented by increasing food intake. This natriuretic-ureotelic, water-conserving principle relies on metabolism-driven extracellular volume control and is regulated by concerted liver, muscle, and renal actions.

Copyright information:

© 2017, American Society for Clinical Investigation

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