High salt intake reprioritizes osmolyte and energy metabolism for body fluid conservation
Kento Kitada, … , Jeff M. Sands, Jens Titze
Kento Kitada, … , Jeff M. Sands, Jens Titze
Published May 18, 2017; First published April 17, 2017
Citation Information: J Clin Invest. 2017;127(5):1944-1959. https://doi.org/10.1172/JCI88532.
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Categories: Research Article Metabolism Nephrology

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

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.

Authors

Kento Kitada, Steffen Daub, Yahua Zhang, Janet D. Klein, Daisuke Nakano, Tetyana Pedchenko, Louise Lantier, Lauren M. LaRocque, Adriana Marton, Patrick Neubert, Agnes Schröder, Natalia Rakova, Jonathan Jantsch, Anna E. Dikalova, Sergey I. Dikalov, David G. Harrison, Dominik N. Müller, Akira Nishiyama, Manfred Rauh, Raymond C. Harris, Friedrich C. Luft, David H. Wasserman, Jeff M. Sands, Jens Titze

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Figure 8

Cardiovascular responses to dietary salt loading.

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Cardiovascular responses to dietary salt loading. Dietary salt levels we...
Dietary salt levels were as follows: black = LS diet; orange = 4% NaCl diet with tap water (HS+tap); red = 4% NaCl diet with additional isotonic saline (HS+saline); green = 4% NaCl diet with isotonic saline and calorie intake restriction (HS+saline, pair-fed). (A) Locomotor activity, heart rate, and SBP in 6 mice over a 21-day period. (B) R-R interval distribution in the same mice after 1 (Day 9) and 4 (Day 12) days of a 4% NaCl diet with isotonic saline. (C) Relationship between heart rate (bpm) and SBP (mmHg) in the same mice. (D) Mean arterial BP (MAP) in acutely restrained mice that were fed a LS (n = 20) or HS+saline (n = 18) diet ad libitum for 2 weeks. *P < 0.05 and **P < 0.01. P(diet): effect of dietary intervention versus LS level; P(day): effect of intervention day; P(inter): interaction between dietary intervention and day of intervention. Data were determined by multivariate analysis of repeated measurements, Student’s t test for paired samples, Student’s t test for independent samples, and by linear regression.