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

• Type of Material: Article
• Authors: Kento Kitada, Vanderbilt University; Steffen Daub, Vanderbilt University; Yahua Zhang, Vanderbilt University; Janet Klein, Emory University; Daisuke Nakano, Kagawa University; Tetyana Pedchenko, Vanderbilt University; Louise Lantier, Vanderbilt University; Lauren M. LaRocque, Emory University; Adriana Marton, Vanderbilt University; Patrick Neubert, University Clinic Erlangen; Agnes Schroeder, University Clinic Erlangen; Natalia Rakova, Charité Medical Faculty; Jonathan Jantsch, University Clinic Erlangen; Anna E. Dikalova, Vanderbilt University; Sergey I. Dikalov, Vanderbilt University; David Harrison, Emory University; Dominik N. Mueller, Charité Medical Faculty; Akira Nishiyama, Kagawa University; Manfred Rauh, University Clinic Erlangen; Raymond C. Harris, Vanderbilt University; Friedrich C. Luft, Vanderbilt University; David H. Wassermann, Vanderbilt University; Jeff Sands, Emory University; Jens Titze, Vanderbilt University
• Language: English
• Date: 2017-05-01
• Publisher: American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: © 2017, American Society for Clinical Investigation
• Final Published Version (URL): http://dx.doi.org/10.1172/JCI88532
• Title of Journal or Parent Work: Journal of Clinical Investigation
• ISSN: 0021-9738
• Volume: 127
• Issue: 5
• Start Page: 1944
• End Page: 1959
• Grant/Funding Information: 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: Metabolism; ESTIVATION; UREA TRANSPORTER; AFRICAN LUNGFISH; AMINO-ACID-METABOLISM; PROTOPTERUS-AETHIOPICUS; ACTIVATED PROTEIN-KINASE; RAT MUSCLE; ACETYL-COA CARBOXYLASE; Research & Experimental Medicine; Medicine, Research & Experimental; IN-VIVO; Nephrology; Science & Technology; PROLONGED STARVATION; Life Sciences & Biomedicine
• Research Categories: Biophysics, General; Health Sciences, Pharmacology; Biology, Physiology

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.