Abstract P245: High-salt Diet Induces Catabolic Urea Formation and Muscle Wasting to Enable Renal Salt Concentration

Abstract

Background: We showed previously that a high salt diet (HSD) increases cortisol levels in man. We hypothesized HSD induces catabolic urea generation to facilitate renal water conservation during dietary salt excretion. Methods: 16 male mice were pair-fed either a low-salt diet (<0.1% NaCl plus tap water) or a HSD (4% NaCl plus 0.9% saline water) for two weeks. We investigated urinary concentration, body weight, MRI lean body mass, tissue urea levels, and enzymatic urea and creatine generation in liver, skeletal muscle, skin and kidney. Results: HSD increased renal Na clearance, decreased urea clearance and resulted in urinary Na concentration. HSD reduced body weight and lean body mass, indicating catabolic muscle wasting. This catabolic state was paralleled by urea accumulation and increased arginase activity in liver and in skeletal muscle, while renal urea excretion was reduced. Expression of L-arginine:glycine amidinotransferase (AGAT), which generates the creatine precursor guanidino-acetate and is representative for anabolic liver/muscle metabolism, was selectively reduced in the livers of HSD mice. Conclusion: HSD induces urea production and body urea accumulation to allow for water-economizing urinary Na concentration. The liver regulates Na homeostasis and induces catabolism by favoring urea over creatine production. Catabolic skeletal muscle serves as a glutamine reservoir for urea generation in HSD mice, resulting in sarcopenia. Perspectives: Cachexia is associated with increased cardiovascular mortality and heart failure in humans. Our findings link this condition to catabolic urea osmolyte generation for maintaining Na balance.