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
Citation Information: J Clin Invest. 2017;127(5):1944-1959. doi: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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Catabolic muscle wasting by experimental salt loading. (A) RQ in mice fe...

Figure 5

Catabolic muscle wasting by experimental salt loading.

(A) RQ in mice fed a 0.1% NaCl chow (LS) (n = 8) or a 4% NaCl chow (n = 8) diet for 7 consecutive days. To test the effect of additional isotonic saline, mice received tap water for 2 days (HS+tap, orange), followed by isotonic saline (HS+saline, red). The activity period at night is shown in gray, and the inactivity period during the daytime is shown in white. Food intake (B) and body weight (C) over a 28-day period of ad libitum feeding, followed by 14 days of pair-feeding with a LS (n = 8) or HS+saline (n = 8) diet. (D) Upper panel: GR binding in the cytoplasm (CP), membrane (M), soluble nuclear fraction (SN), chromatin-bound GR (CB), and cytoskeletal (CS) GR in the subcellular fraction in skeletal muscle in mice fed a LS (n = 5) or HS+saline (n = 5) diet. Lower panel: Protein expression of LC3 in its cytosolic form (LC3-I) and as its LC-3-phosphatidylethanolamine conjugate (LC3-II) in the muscle of mice fed a LS (n = 4) or HS+saline (n = 4) diet. (E) Quantification of chromatin-bound GR protein expression and ratio of LC3-II/LC3-I protein expression in mice fed a LS (n = 5) or HS+saline (n = 5) diet. (F) Plasma corticosterone levels in mice fed a LS (n = 8) or HS+saline (n = 8) diet. (G) Relationship between changes (Δ) in body weight and muscle mass, as measured by magnetic resonance lean tissue mass, in mice fed a LS (n = 8) or HS+saline (n = 8) diet. (H) In vivo detection of LC3 expression (green) in skeletal muscle of LC3-GFP mice after pair-feeding on a LS or HS+saline diet. Data were determined by multivariate analysis of repeated measurements, by Student’s t test for independent samples, or by linear regression.