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

• 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
• Journal Title: Journal of Clinical Investigation
• Volume: Volume 127, Number 5
• Publisher: American Society for Clinical Investigation | 2017-05-01, Pages 1944-1959
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1172/JCI88532
• Subjects: Health Sciences, Pharmacology; Biology, Physiology; Biophysics, General
• 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

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.