抄録
Backgrounds: We recently reported that the body differentially controls its body fluid content by natriuretic-ureotelic regulation, which is characterized by a balance between aldosterone/Na+-driven or glucocorticoid/urea-driven water reabsorption in the biological barriers. We hypothesized that mice with elevated glucocorticoids shift this balance in favor of urea-driven water conservation and show decreased Na+ storage in the body.
Methods: We fed melanocortin-3-receptor (MC3R) knockout (KO) mice, which have elevated glucocorticoid levels, and wild-type (WT) control mice a low-salt diet (0.1% NaCl plus tap water) for 4 weeks. We studied 24-h osmolyte excretion and concentration in urine. We also measured body composition, tissue osmolytes and water content, glucocorticoid-receptor (GR) protein/chromatin interaction, and arginase activity for urea production.
Results: MC3R-KO mice showed increased GR chromatin binding in skeletal muscle with reduced muscle mass and increased fat content, confirming endogenous glucocorticoid excess. MC3R-KO mice increased urea transporter (UT) A1 protein and urea content in the renal medulla, which was coupled with reduced urinary urea excretion and lower urine volume, while urinary Na+ excretion and urine osmolyte concentrations were similar to WT mice. MC3R-KO mice also showed increased arginase activity in skeletal muscle, but not in liver, kidney, or skin. Total body Na+ and water content were decreased in MC3R-KO mice because of reduced skin Na+ and water content. These skin-specific Na+ and water reductions were associated with high lymphatic vessel endothelial hyaluronan receptor-1 mRNA levels in the skin, suggesting that expanded cutaneous lymph vessels enhanced lymphatic osmolyte and water clearance in MC3R-KO mice. In line with our hypothesis, MC3R-KO mice increased skin urea content and reduced cutaneous Na+ content. This skin Na+ loss was not compensated by skin urea accumulation, resulting in reduced skin osmolyte content and cutaneous water loss.
Conclusions: Our findings confirm that fluid homeostasis is maintained by natriuretic-ureotelic regulation in kidney and skin. In MC3R-KO with central hypercortisolism, medullary urea osmolyte accumulation allows efficient renal water conservation. However, in the skin barrier, increased urea-driven water conservation is not sufficient to compensate for reduced skin Na+ accumulation, resulting in skin-specific water loss that reduces total body water content.
