TY - JOUR AU - Kitada, Kento AU - Daub, Steffen AU - Zhang, Yahua AU - Klein, Janet D. AU - Nakano, Daisuke AU - Pedchenko, Tetyana AU - Lantier, Louise AU - LaRocque, Lauren M. AU - Marton, Adriana AU - Neubert, Patrick AU - Schröder, Agnes AU - Rakova, Natalia AU - Jantsch, Jonathan AU - Dikalova, Anna E. AU - Dikalov, Sergey I. AU - Harrison, David G. AU - Müller, Dominik N. AU - Nishiyama, Akira AU - Rauh, Manfred AU - Harris, Raymond C. AU - Luft, Friedrich C. AU - Wasserman, David H. AU - Sands, Jeff M. AU - Titze, Jens T1 - High salt intake reprioritizes osmolyte and energy metabolism for body fluid conservation PY - 2017/05/18/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI88532 VL - 127 IS - 5 UR - https://doi.org/10.1172/JCI88532 SP - 1944 EP - 1959 PB - The American Society for Clinical Investigation ER -