Spector DA, Deng J, Stewart KJ. Dietary protein affects urea transport across rat urothelia. Am J Physiol Renal Physiol 303: F944-F953, 2012. First published July 25, 2012 doi:10.1152/ajprenal.00238.2012.-Recent evidence suggests that regulated solute transport occurs across mammalian lower urinary tract epithelia (urothelia). To study the effects of dietary protein on net urothelial transport of urea, creatinine, and water, we used an in vivo rat bladder model designed to mimic physiological conditions. We placed groups of rats on 3-wk diets differing only by protein content (40,18,6, and 2%) and instilled 0.3 ml of collected urine in the isolated bladder of anesthetized rats. After 1 h dwell, retrieved urine volumes were unchanged, but mean urea nitrogen (UN) and creatinine concentrations fell 17 and 4%, respectively, indicating transurothelial urea and creatinine reabsorption. The fall in UN (but not creatinine) concentration was greatest in high protein (40%) rats, 584 mg/dl, and progressively less in rats receiving lower protein content: 18% diet, 224 mg/dl; 6% diet, 135 mg/dl; and 2% diet, 87 mg/dl. The quantity of urea reabsorbed was directly related to a urine factor, likely the concentration of urea in the instilled urine. In contrast, the percentage of instilled urea reabsorbed was greater in the two dietary groups receiving the lowest protein (26 and 23%) than in those receiving higher protein (11 and 9%), suggesting the possibility that a bladder/urothelial factor, also affected by dietary protein, may have altered bladder permeability. These findings demonstrate significant regulated urea transport across the urothelium, resulting in alteration of urine excreted by the kidneys, and add to the growing evidence that the lower urinary tract may play an unappreciated role in mammalian solute homeostasis.solute transport across bladder epithelia; urothelial creatinine transport; regulation of urothelial urea transport ALTHOUGH MAMMALIAN LOWER URINARY tract functions primarily as a short-term transit and storage vehicle for urine made by the kidneys (13), recent data demonstrate that mammalian urothelia (the epithelial cell lining of the urinary tract from renal pelvis to proximal urethra) is a surprisingly dynamic and complex tissue that may play an unappreciated role in water and solute homeostasis (35)(36)(37)(38)(39) reviewed in Ref. 22). While the urothelial permeability barriers, thought to reside in the apical membrane of the large "umbrella" cells lining the urinary tract lumens, the tight junction (TJ) between those cells, and the adherent overlying urinary glycosaminoglycans (GAG) layer (18,19,22,24,48), have been shown in vitro to have low permeability to water, urea, and ions (9,25,28), there are a number of physiological factors that might be expected to promote (even) passive diffusion of water and solutes across these barriers, including the large urinary tract lumenal surface area, long storage time of urine, enormous and changing concentration gradients for water, solutes, and ions, and ...