Urea may regulate urea transporter protein abundance during osmotic diuresis

Abstract

Rats with diabetes mellitus have an increase in UT-A1 urea transporter protein abundance and absolute urea excretion, but the relative amount (percentage) of urea in total urinary solute is actually decreased due to the marked glucosuria. Urea-specific signaling pathways have been identified in mIMCD3 cells and renal medulla, suggesting the possibility that changes in the percentage or concentration of urea could be a factor that regulates UT-A1 abundance. In this study, we tested the hypothesis that an increase in a urinary solute other than urea would increase UT-A1 abundance, similar to diabetes mellitus, whereas an increase in urine urea would not. In both inner medullary base and tip, UT-A1 protein abundance increased during NaCl-or glucose-induced osmotic diuresis but not during urea-induced osmotic diuresis. Next, rats undergoing NaCl or glucose diuresis were given supplemental urea to increase the percentage of urine urea to control values. UT-A1 abundance did not increase in these urea-supplemented rats compared with control rats. Additionally, both UT-A2 and UT-B protein abundances in the outer medulla increased during urea-induced osmotic diuresis but not in NaCl or glucose diuresis. We conclude that during osmotic diuresis, UT-A1 abundance increases when the percentage of urea in total urinary solute is low and UT-A2 and UT-B abundances increase when the urea concentration in the medullary interstitium is high. These findings suggest that a reduction in urine or interstitial urea results in an increase in UT-A1 protein abundance in an attempt to restore inner medullary interstitial urea and preserve urine-concentrating ability.sodium-potassium-2 chloride cotransporter; diabetes mellitus THE RENAL MEDULLA IS THE LOCATION in which water excretion is controlled through the production of concentrated or dilute urine. Several solute transport proteins play a major role in the urinary concentrating mechanism, including urea transporters and the NaϪ cotransporter (NKCC2/BSC1). Among the urea transporters, UT-A1 is expressed in the inner medullary collecting duct and is important for vasopressin-regulated urea reabsorption (reviewed in Ref. 21). UT-A2 and UT-B are expressed in the thin descending limb and descending vasa recta, respectively, and are important for intrarenal urea recycling (reviewed in Ref. 21). NKCC2/BSC1 is expressed in the thick ascending limb of the loop of Henle and is responsible for the active reabsorption of NaCl that drives the single effect to concentrate urine (reviewed in Ref. 22).Several studies show that UT-A1, as well as NKCC2/BSC1 and aquaporin-2 (AQP2), protein abundances increase after 5 days of uncontrolled diabetes mellitus due to streptozotocin (2,10,11,19,27). We showed that UT-A1 protein abundance does not change in streptozotocin-treated Brattleboro rats, indicating that vasopressin is necessary for the increase in UT-A1 protein abundance because Brattleboro rats lack vasopressin (11). When we administered vasopressin to Brattleboro rats and then induced diabetes melli...

Diabetes induced renal urea transport alterations assessed with 3D hyperpolarized13C,15N-Urea

“…Diabetes Induced Renal Urea Transport Alterations Assessed With 3D Hyperpolarized 13 C, 15 the control kidney, (P < 0.0001) (Fig. 2).…”

“…Thus, we speculate that this increase is to compensate for the reduced concentrating ability in the diabetic kidney. Likewise, as UT-A2 and UT-B compensate for the action of the each other, the increase observed in UT-B and thereby a decrease in UT-A2 may result from a challenge to restore inner medullary interstitial urea, which is disrupted even in the early stage of diabetes (11,13,15). Although changes are observed both in urea gradient and urea transporter expression, the NGAL marker included in this study indicated that no kidney injury can be seen in the early stages of diabetes.…”

“…The MR examination was performed with a preclinical MR system 9.4 Tesla (T) (Agilent, Yarnton, UK) equipped with a dual tuned 13 C/ 1 H volume rat coil (Doty Scientific, Columbia, SC). A total of 200 mL of [ 13 C, 15 N]urea (Sigma-Aldrich, Brøndby, DK), glycerol (Sigma-Aldrich, Brøndby, DK), and AH111501 (GE Healthcare, Brøndby, DK) (6.4 M concentration) were mixed with weight ratio (0.30:0.68:0.02) and was polarized in a 5T SPINLab (GE Healthcare, Brøndby, DK) to a reproducible polarization of more than 40% (17). The hyperpolarized sample was rapidly dissolved and a final solution of 1.5 mL hyperpolarized 145 mM [ 13 (Fig.…”

Glycogen levels and energy status of the liver of fasting rats with diabetes types 1 and 2

“…The ammonia and urea concentrations of the rats with diabetes2 were normal, but rats with diabetes1 presented considerably higher urea (+401.5%) and ammonia (+90.9%) concentrations. These higher blood urea and ammonia concentrations in rats with diabetes1 are probably reflecting the higher rates of amino acid degradation (Squires et al, 1997), which also increase the urinary urea excretion (Kim et al, 2005). However, the increased urea excretion was combined with a much higher urinary volume and lower urinary urea concentrations (Kim et al, 2005).…”

“…These higher blood urea and ammonia concentrations in rats with diabetes1 are probably reflecting the higher rates of amino acid degradation (Squires et al, 1997), which also increase the urinary urea excretion (Kim et al, 2005). However, the increased urea excretion was combined with a much higher urinary volume and lower urinary urea concentrations (Kim et al, 2005). The high blood urea concentrations are, thus, the consequence of both higher amino acid catabolism and impaired renal function.…”