Skip to main content
SpringerLink
Log in

Molecular mechanisms of urea transport in health and disease

  • Invited Review
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

In the late 1980s, urea permeability measurements produced values that could not be explained by paracellular transport or lipid phase diffusion. The existence of urea transport proteins were thus proposed and less than a decade later, the first urea transporter was cloned. The family of urea transporters has two major subgroups, designated SLC14A1 (or UT-B) and Slc14A2 (or UT-A). UT-B and UT-A gene products are glycoproteins located in various extra-renal tissues however, a majority of the resulting isoforms are found in the kidney. The UT-B (Slc14A1) urea transporter was originally isolated from erythrocytes and two isoforms have been reported. In kidney, UT-B is located primarily in the descending vasa recta. The UT-A (Slc14A2) urea transporter yields six distinct isoforms, of which three are found chiefly in the kidney medulla. UT-A1 and UT-A3 are found in the inner medullary collecting duct (IMCD), while UT-A2 is located in the thin descending limb. These transporters are crucial to the kidney’s ability to concentrate urine. The regulation of urea transporter activity in the IMCD involves acute modification through phosphorylation and subsequent movement to the plasma membrane. UT-A1 and UT-A3 accumulate in the plasma membrane in response to stimulation by vasopressin or hypertonicity. Long-term regulation of the urea transporters in the IMCD involves altering protein abundance in response to changes in hydration status, low protein diets, or adrenal steroids. Urea transporters have been studied using animal models of disease including diabetes mellitus, lithium intoxication, hypertension, and nephrotoxic drug responses. Exciting new genetically engineered mouse models are being developed to study these transporters.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Ahloulay M, Bouby N, Machet F, Kubrusly M, Coutaud C, Bankir L (1992) Effects of glucagon on glomerular filtration rate and urea and water excretion. Am J Physiol Renal, Fluid Electrolyte Physiol 263:F24–F36

    CAS  Google Scholar 

  2. Ahloulay M, Déchaux M, Laborde K, Bankir L (1995) Influence of glucagon on GFR and on urea and electrolyte excretion: direct and indirect effects. Am J Physiol Renal, Fluid Electrolyte Physiol 269:F225–F235

    CAS  Google Scholar 

  3. Anderson MO, Zhang J, Liu Y, Yao C, Phuan PW, Verkman AS (2012) Nanomolar potency and metabolically stable inhibitors of kidney urea transporter UT-B. J Med Chem 55(12):5942–5950. doi:10.1021/jm300491y

    Article  CAS  PubMed  Google Scholar 

  4. Bardoux P, Ahloulay M, Le Maout S, Bankir L, Trinh-Trang-Tan MM (2001) Aquaporin-2 and urea transporter-A1 are up-regulated in rats with type I diabetes mellitus. Diabetologia 44(5):637–645

    Article  CAS  PubMed  Google Scholar 

  5. Bedford JJ, Leader JP, Jing R, Walker LJ, Klein JD, Sands JM, Walker RJ (2008) Amiloride restores renal medullary osmolytes in lithium-induced nephrogenic diabetes insipidus. Am J Physiol Renal Physiol 294(4):F812–F820

    Article  CAS  PubMed  Google Scholar 

  6. Bickel CA, Knepper MA, Verbalis JG, Ecelbarger CA (2002) Dysregulation of renal salt and water transport proteins in diabetic Zucker rats. Kidney Int 61(6):2099–2110

    Article  CAS  PubMed  Google Scholar 

  7. Blessing NW, Blount MA, Sands JM, Martin CF, Klein JD (2008) Urea transporters UT-A1 and UT-A3 accumulate in the plasma membrane in response to increased hypertonicity. Am J Physiol Renal Physiol 295(5):F1336–F1341

    Article  CAS  PubMed  Google Scholar 

  8. Blount MA, Klein JD, Martin CF, Tchapyjnikov D, Sands JM (2007) Forskolin stimulates phosphorylation and membrane accumulation of UT-A3. Am J Physiol Renal Physiol 293(4):F1308–F1313

    Article  CAS  PubMed  Google Scholar 

  9. Blount MA, Mistry AC, Fröhlich O, Price SR, Chen G, Sands JM, Klein JD (2008) Phosphorylation of UT-A1 urea transporter at serines 486 and 499 is important for vasopressin-regulated activity and membrane accumulation. Am J Physiol Renal Physiol 295(1):F295–F299

    Article  CAS  PubMed  Google Scholar 

  10. Blount MA, Sands JM, Kent KJ, Smith TD, Price SR, Klein JD (2008) Candesartan augments compensatory changes in medullary transport proteins in the diabetic rat kidney. Am J Physiol Renal Physiol 285(6):F1448–F1452

    Article  Google Scholar 

  11. Blount MA, Sim JH, Zhou R, Martin CF, Lu W, Sands JM, Klein JD (2010) The expression of transporters involved in urine concentration recover differently after ceasing lithium treatment. Am J Physiol Renal Physiol 298:F601–F608

    Article  CAS  PubMed  Google Scholar 

  12. Bou Matar RN, Malik B, Wang XH, Martin CF, Eaton DC, Sands JM, Klein JD (2012) Protein abundance of urea transporters and aquaporin 2 change differently in nephrotic pair-fed versus non-pair-fed rats. Am J Physiol Renal Physiol 302:F1545–F1553

    Article  CAS  PubMed  Google Scholar 

  13. Brooks DD, Nutting DF, Crofton JT, Share L (1989) Vasopressin in rats with genetic and streptozotocin-induced diabetes. Diabetes 38:54–57

    Article  CAS  PubMed  Google Scholar 

  14. Chen G, Howe AG, Xu G, Froehlich O, Klein JD, Sands JM (2011) Mature N-linked glycans facilitate UT-A1 urea transporter lipid raft compartmentalization. FASEB J 25:4531–4539

    Article  CAS  PubMed  Google Scholar 

  15. Chen YC, Cadnapaphornchai MA, Summer SN, Falk S, Li C, Wang W, Schrier RW (2005) Molecular mechanisms of impaired urinary concentrating ability in glucocorticoid-deficient rats. J Am Soc Nephrol 16(10):2864–2871

    Article  CAS  PubMed  Google Scholar 

  16. Cipriani P, Kim SL, Klein JD, Sim JH, von Bergen TN, Blount MA (2012) The role of nitric oxide in the dysregulation of the urine concentration mechanism in diabetes mellitus. Front Physiol 3:176. doi:10.3389/fphys.2012.00176

    Article  PubMed  Google Scholar 

  17. Combet S, Geffroy N, Berthonaud V, Dick B, Teillet L, Verbavatz J-M, Corman B, Trinh-Trang-Tan M-M (2003) Correction of age-related polyuria by dDAVP: molecular analysis of aquaporins and urea transporters. Am J Physiol Renal Physiol 284(1):F199–F208

    CAS  PubMed  Google Scholar 

  18. Combet S, Teillet L, Geelen G, Pitrat B, Gobin R, Nielsen S, Trinh-Trang-Tan MM, Corman B, Verbavatz JM (2001) Food restriction prevents age-related polyuria by vasopressin-dependent recruitment of aquaporin-2. Am J Physiol: Renal Physiol 281(6):F1123–F1131

    CAS  Google Scholar 

  19. Dousa TP (1974) Interaction of lithium with vasopressin-sensitive cyclic AMP system of human renal medulla. Endocrinology 95:1359–1366

    Article  CAS  PubMed  Google Scholar 

  20. Ecelbarger CA, Sands JM, Doran JJ, Cacini W, Kishore BK (2001) Expression of salt and urea transporters in rat kidney during cisplatin-induced polyuria. Kidney Int 60(6):2274–2282

    Article  CAS  PubMed  Google Scholar 

  21. Esther CR Jr, Marrero MB, Howard TE, Machaud A, Corvol P, Capecchi MR, Bernstein KE (1997) The critical role of tissue angiotensin-converting enzyme as revealed by gene targeting in mice. JClinInvset 99:2375–2385

    CAS  Google Scholar 

  22. Faubert PF, Chou SY, Porush JG, Byrd R (1987) Regulation of papillary plasma flow by angiotensin II. Kidney Int 32:472–478

    Article  CAS  PubMed  Google Scholar 

  23. Fenton RA (2008) Urea transporters and renal function: lessons from knockout mice. Curr Opin Nephrol Hypertens 17:513–518

    Article  PubMed  Google Scholar 

  24. Fenton RA, Brond L, Nielsen S, Praetorius J (2007) Cellular and subcellular distribution of the type II vasopressin receptor in kidney. Am J Physiol Renal Physiol 293:F748–F760

    Article  CAS  PubMed  Google Scholar 

  25. Fenton RA, Chou C-L, Ageloff S, Brandt W, Stokes JB III, Knepper M (2003) Increased collecting duct urea transporter expression in Dahl salt-sensitive rats. Am J PhysiolRenal Physiol 285(1):F143–F151

    CAS  Google Scholar 

  26. Fenton RA, Chou C-L, Stewart GS, Smith CP, Knepper MA (2004) Urinary concentrating defect in mice with selective deletion of phloretin-sensitive urea transporters in the renal collecting duct. Proc Natl Acad Sci U S A 101(19):7469–7474

    Article  CAS  PubMed  Google Scholar 

  27. Fenton RA, Chou CL, Sowersby H, Smith CP, Knepper MA (2006) Gamble’s “economy of water” revisited: studies in urea transporter knockout mice. AmJ Physiol Renal Physiol 291(1):F148–F154

    Article  CAS  Google Scholar 

  28. Fenton RA, Flynn A, Shodeinde A, Smith CP, Schnermann J, Knepper MA (2005) Renal phenotype of UT-A urea transporter knockout mice. J Am Soc Nephrol 16(6):1583–1592

    Article  CAS  PubMed  Google Scholar 

  29. Fenton RA, Knepper MA (2007) Urea and renal function in the 21st century: insights from knockout mice. J Am Soc Nephrol 18(3):679–688

    Article  CAS  PubMed  Google Scholar 

  30. Fernández-Llama P, Andrews P, Nielsen S, Ecelbarger CA, Knepper MA (1998) Impaired aquaporin and urea transporter expression in rats with adriamycin-induced nephrotic syndrome. Kidney Int 53(5):1244–1253

    Article  PubMed  Google Scholar 

  31. Galluci E, Micelli S, Lippe C (1971) Non-electrolyte permeability across thin lipid membranes. Arch Int Physiol Biochim 79:881–887

    Article  Google Scholar 

  32. Gamble JL, McKhann CF, Butler AM, Tuthill E (1934) An economy of water in renal function referable to urea. Am J Physiol 109:139–154

    CAS  Google Scholar 

  33. Gertner R, Klein JD, Bailey JL, Kim D-U, Luo X, Bagnasco SM, Sands JM (2004) Aldosterone decreases UT-A1 urea transporter expression via the mineralocorticoid receptor. J Am Soc Nephrol 15(3):558–565

    Article  CAS  PubMed  Google Scholar 

  34. Harrington AR, Valtin H (1968) Impaired urinary concentration after vasopressin and its gradual correction in hypothalamic diabetes insipidus. J Clin Invest 47:502–510

    Article  CAS  PubMed  Google Scholar 

  35. Ilori TO, Wang Y, Blount MA, Martin CF, Sands JM, Klein JD (2012) Acute calcineurin inhibition with tacrolimus increases phosphorylated UT-A1. Am J Physiol Renal Physiol 302:F998–F1004

    Article  CAS  PubMed  Google Scholar 

  36. Isozaki T, Gillin AG, Swanson CE, Sands JM (1994) Protein restriction sequentially induces new urea transport processes in rat initial IMCDs. Am J Physiol 266:F756–F761

    CAS  PubMed  Google Scholar 

  37. Jackson BA, Braun-Werness JL, Kusano E, Dousa TP (1983) Concentrating defect in the adrenalectomized rat. Abnormal vasopressin-sensitive cyclic adenosine monophosphate metabolism in the papillary collecting duct. J Clin Invest 72:997–1004

    Article  CAS  PubMed  Google Scholar 

  38. Jacob VA, Harbaugh CM, Dietz JR, Fenton RA, Kim SM, Castrop H, Schnermann J, Knepper MA, Chou CL, Anderson SA (2008) Magnetic resonance imaging of urea transporter knockout mice shows renal pelvic abnormalities. Kidney Int 74(9):1202–1208

    Article  CAS  PubMed  Google Scholar 

  39. Kamoi K, Tamura T, Tanaka K, Ishikashi M, Yamagi T (1993) Hyponatremia and osmoregulation of thirst and vasopressin secretion in patients with adrenal insufficiency. J Clin Endocrin Metabol 77:1584–1588

    Article  CAS  Google Scholar 

  40. Kato A, Sands JM (1998) Evidence for sodium-dependent active urea secretion in the deepest subsegment of the rat inner medullary collecting duct. J Clin Invest 101(2):423–428

    Article  CAS  PubMed  Google Scholar 

  41. Kim D-U, Sands JM, Klein JD (2003) Changes in renal medullary transport proteins during uncontrolled diabetes mellitus in rats. Am J Physiol Renal Physiol 285(2):F303–F309

    CAS  PubMed  Google Scholar 

  42. Kim D-U, Sands JM, Klein JD (2004) Role of vasopressin in diabetes mellitus-induced changes in medullary transport proteins involved in urine concentration in Brattleboro rats. Am J Physiol Renal Physiol 286:F760–F766

    Article  CAS  PubMed  Google Scholar 

  43. Klein JD, Blount MA, Sands JM (2011) Urea transport in the kidney. Compr Physiol 1(2):699–729

    Google Scholar 

  44. Klein JD, Fröhlich O, Blount MA, Martin CF, Smith TD, Sands JM (2006) Vasopressin increases plasma membrane accumulation of urea transporter UT-A1 in rat inner medullary collecting ducts. J Am Soc Nephrol 17:2680–2686

    Article  CAS  PubMed  Google Scholar 

  45. Klein JD, Gunn RB, Roberts BR, Sands JM (2002) Down-regulation of urea transporters in the renal inner medulla of lithium-fed rats. Kidney Int 61(3):995–1002

    Article  CAS  PubMed  Google Scholar 

  46. Klein JD, Martin CF, Kent KJ, Sands JM (2012) Protein kinase C alpha mediates hypertonicity-stimulated increase in urea transporter phosphorylation in the inner medullary collecting duct. AmJPhysiol Renal Physiol 302:in press

  47. Klein JD, Murrell BP, Tucker S, Kim Y-H, Sands JM (2006) Urea transporter UT-A1 and aquaporin-2 proteins decrease in response to angiotensin II or norepinephrine-induced acute hypertension. Am J Physiol Renal Physiol 291(5):F952–F959

    Article  CAS  PubMed  Google Scholar 

  48. Klein JD, Price SR, Bailey JL, Jacobs JD, Sands JM (1997) Glucocorticoids mediate a decrease in the AVP-regulated urea transporter in diabetic rat inner medulla. Am J Physiol 273(6):F949–F953

    CAS  PubMed  Google Scholar 

  49. Klein JD, Quach DL, Cole JM, Disher K, Mongiu AK, Wang X, Bernstein KE, Sands JM (2002) Impaired urine concentration and the absence of tissue ACE: the involvement of medullary transport proteins. Am J Physiol Renal Physiol 283(3):F517–F524

    CAS  PubMed  Google Scholar 

  50. Klein JD, Sands JM, Qian L, Wang X, Yang B (2004) Upregulation of urea transporter UT-A2 and water channels AQP2 and AQP3 in mice lacking urea transporter UT-B. J Am Soc Nephrol 15(5):1161–1167

    Article  CAS  PubMed  Google Scholar 

  51. Knepper MA, Danielson RA, Saidel GM, Johnston KH (1975) Effects of dietary protein restriction and glucocorticoid administration on urea excretion in rats. Kidney Int 8:303–315

    Article  CAS  PubMed  Google Scholar 

  52. Knepper MA, Gunter CV, Danielson RA (1976) Effects of glucagon on renal function in protein-deprived rats. Surg Forum 27:29–31

    CAS  PubMed  Google Scholar 

  53. Kuper C, Fraek ML, Muller HH, Beck FX, Neuhofer W (2012) Sepsis-induced urinary concentration defect is related to nitric oxide-dependent inactivation of TonEBP/NFAT5, which downregulates renal medullary solute transport proteins and aquaporin-2. Crit Care Med 40(6):1887–1895. doi:10.1097/CCM.0b013e31824e118600003246-201206000-00027

    Article  PubMed  Google Scholar 

  54. Lei T, Zhou L, Layton AT, Zhou H, Zhao X, Bankir L, Yang B (2011) Role of thin descending limb urea transport in renal urea handling and the urine concentrating mechanism. Am J Physiol Renal Physiol 301(6):F1251–F1259

    Article  CAS  PubMed  Google Scholar 

  55. Li C, Klein JD, Wang W, Knepper MA, Nielsen S, Sands JM, Frokiaer J (2004) Altered expression of urea transporters in response to ureteral obstruction. Am J Physiol Renal Physiol 286(6):F1154–F1162

    Article  CAS  PubMed  Google Scholar 

  56. Li C, Wang W, Summer SN, Falk S, Schrier RW (2008) Downregulation of UT-A1/UT-A3 Is Associated with Urinary Concentrating Defect in Glucocorticoid-Excess State. J Am Soc Nephrol 19(10):1975–1981

    Article  CAS  PubMed  Google Scholar 

  57. Li X, Chen G, Yang B (2012) Urea Transporter Physiology Studied in Knockout Mice. Frontiers in Physiology 3

  58. Lim S-W, Han K-H, Jung J-Y, Kim W-Y, Yang C-W, Sands JM, Knepper MA, Madsen KM, Kim J (2006) Ultrastructural localization of UT-A and UT-B in rat kidneys with different hydration status. Am J Physiol Regul Integr Comp Physiol 290(2):R479–R492

    Article  CAS  PubMed  Google Scholar 

  59. Lim S-W, Li C, Sun B-K, Kim W-Y, Han K-H, Oh Y-W, Lee J-U, Kador PF, Knepper MA, Sands JM, Kim J, Yang C-W (2004) Long-term treatment with cyclosporine decreases aquaporins and urea transporters in rat kidney. Am J Physiol Renal Physiol 287(1):F139–F151

    Article  CAS  PubMed  Google Scholar 

  60. Macey RI (1984) Transport of water and urea in red blood cells. Am J Physiol 246:C195–C203

    CAS  PubMed  Google Scholar 

  61. Maeda Y, Terada Y, Nonoguchi H, Knepper MA (1992) Hormone and autocoid regulation of cAMP production in rat IMCD subsegments. Am J Physiol 263:F319–F327

    CAS  PubMed  Google Scholar 

  62. Marples D, Christensen S, Christensen EI, Ottosen PD, Nielsen S (1995) Lithium-induced downregulation of Aquaporin-2 water channel expression in rat kidney medulla. J Clin Invest 95:1838–1845

    Article  CAS  PubMed  Google Scholar 

  63. Mitch WE, Bailey JL, Wang X, Jurkovitz C, Newby DN, Price SR (1999) Evaluation of signals activating ubiquitin-proteasome proteolysis in a model of muscle wasting. Am J Physiol Cell Physiol 276:C1132–C1138

    CAS  Google Scholar 

  64. Nakayama Y, Peng T, Sands JM, Bagnasco SM (2000) The TonE/TonEBP pathway mediates tonicity-responsive regulation of UT-A urea transporter expression. JBiolChem 275(49):38275–38280

    CAS  Google Scholar 

  65. Naruse M, Klein JD, Ashkar ZM, Jacobs JD, Sands JM (1997) Glucocorticoids downregulate the rat vasopressin-regulated urea transporter in rat terminal inner medullary collecting ducts. JAmSocNephrol 8(4):517–523

    CAS  Google Scholar 

  66. Nielsen J, Hoffert JD, Knepper MA, Agre P, Nielsen S, Fenton RA (2008) Proteomic analysis of lithium-induced nephrogenic diabetes insipidus: mechanisms for aquaporin 2 down-regulation and cellular proliferation. Proc Natl Acad Sci 105(9):3634–3639

    Article  CAS  PubMed  Google Scholar 

  67. Pech V, Klein JD, Kozlowski SD, Wall SM, Sands JM (2005) Vasopressin increases urea permeability in initial IMCDs from diabetic rats. Am J Physiol Renal Physiol 289(3):F531–F535

    Article  CAS  PubMed  Google Scholar 

  68. Peng T, Sands JM, Bagnasco SM (2002) Glucocorticoids inhibit transcription and expression of the rat UT-A urea transporter gene. Am J Physiol Renal Physiol 282(5):F853–F858

    CAS  PubMed  Google Scholar 

  69. Preisser L, Teillet L, Aliotti S, Gobin R, Berthonaud V, Chevalier J, Corman B, Verbavatz JM (2000) Downregulation of aquaporin-2 and-3 in aging kidney is independent of V2 vasopressin receptor. Am J Physiol: Renal Physiol 279(1):F144–F152

    CAS  Google Scholar 

  70. Promeneur D, Bankir L, Hu MC, Trinh-Trang-Tan M-M (1998) Renal tubular and vascular urea transporters: influence of antidiuretic hormone on messenger RNA expression in Brattleboro rats. J Am Soc Nephrol 9(8):1359–1366

    CAS  PubMed  Google Scholar 

  71. Sanches TR, Volpini RA, Massola Shimizu MH, Braganca AC, Oshiro-Monreal F, Seguro AC, Andrade L (2012) Sildenafil reduces polyuria in rats with lithium-induced NDI. Am J Physiol Renal Physiol 302(1):F216–F225. doi:10.1152/ajprenal.00439.2010

    Article  CAS  PubMed  Google Scholar 

  72. Sands JM (2007) Critical role of urea in the urine-concentrating mechanism. J Am Soc Nephrol 18(3):670–671

    Article  CAS  PubMed  Google Scholar 

  73. Sands JM (2012) Urine concentrating and diluting ability during aging. J Gerontol A Biol Med Sci, in press

  74. Sands JM, Gargus JJ, Fröhlich O, Gunn RB, Kokko JP (1992) Urinary concentrating ability in patients with Jk(a-b-) blood type who lack carrier-mediated urea transport. J Am Soc Nephrol 2:1689–1696

    CAS  PubMed  Google Scholar 

  75. Sands JM, Nonoguchi H, Knepper MA (1987) Vasopressin effects on urea and H2O transport in inner medullary collecting duct subsegments. Am J Physiol 253:F823–F832

    CAS  PubMed  Google Scholar 

  76. Sands JM, Timmer RT, Gunn RB (1997) Urea transporters in kidney and erythrocytes. Am J Physiol 273(3):F321–F339

    CAS  PubMed  Google Scholar 

  77. Schwartz MJ, Kokko JP (1980) Urinary concentrating defect of adrenal insufficiency. Permissive role of adrenal steroids on the hydroosmotic response across the rabbit cortical collecting duct. J Clin Invest 66:234–242

    Article  CAS  PubMed  Google Scholar 

  78. Smith CP, Potter EA, Fenton RA, Stewart GS (2004) Characterization of a human colonic cDNA encoding a structurally novel urea transporter, UT-A6. Am J Physiol Cell Physiol 287(4):C1087–C1093

    Article  CAS  PubMed  Google Scholar 

  79. Su H, Carter CB, Frohlich O, Cummings RD, Chen G (2012) Glycoforms of UT-A3 urea transporter with poly-N-acetyllactosamine glycosylation have enhanced transport activity. Am J Physiol Renal Physiol 303(2):F201–208. doi:10.1152/ajprenal.00140.2012

    Article  CAS  PubMed  Google Scholar 

  80. Terris J, Ecelbarger CA, Sands JM, Knepper MA (1998) Long-term regulation of collecting duct urea transporter proteins in rat. J Am Soc Nephrol 9(5):729–736

    CAS  PubMed  Google Scholar 

  81. Thai TL, Blount MA, Klein JD, Sands JM (2012) Lack of protein kinase C-α leads to impaired urine concentrating ability and decreased aquaporin-2 in angiotensin II-induced hypertension. Am J Physiol Renal Physiol 303(1):F37–F44

    Article  CAS  PubMed  Google Scholar 

  82. Tickle P, Thistlethwaite A, Smith CP, Stewart GS (2009) Novel bUT-B2 urea transporter isoform is constitutively activated. AJP - Regul, Integr Comp Physiol 297(2):R323–R329

    Article  CAS  Google Scholar 

  83. Timmer RT, Sands JM (1999) Lithium intoxication. J Am Soc Nephrol 10(3):666–674

    CAS  PubMed  Google Scholar 

  84. Trinder D, Phillips PA, Stephenson JM, Risvanis J, Aminian A, Adam W, Cooper M, Johnston CI (1994) Vasopressin V1 and V2 receptors in diabetes mellitus. Am J Physiol Endocrinol Metab 266:E217–E223

    CAS  Google Scholar 

  85. Trinh-Trang-Tan M-M, Lasbennes F, Gane P, Roudier N, Ripoche P, Cartron J-P, Bailly P (2002) UT-B1 proteins in rat: tissue distribution and regulation by antidiuretic hormone in kidney. Am J Physiol Renal Physiol 283(5):F912–F922

    PubMed  Google Scholar 

  86. Trinh-Trang-Tan MM, Geelen G, Teillet L, Corman B (2003) Urea transporter expression in aging kidney and brain during dehydration. Am J Physiol Regul Integr Comp Physiol 285(6):R1355–R1365

    CAS  PubMed  Google Scholar 

  87. Uchida S, Sohara E, Rai T, Ikawa M, Okabe M, Sasaki S (2005) Impaired urea accumulation in the inner medulla of mice lacking the urea transporter UT-A2. Mol Cell Biol 25(16):7357–7363

    Article  CAS  PubMed  Google Scholar 

  88. Van Zwieten PA, Kam KL, Pijl AJ, Hendriks MGC, Beenen OHM, Pfaffendorf M (1996) Hypertensive diabetic ratsin pharmacological studies. Pharmacol Res 33(2):95–105

    Article  PubMed  Google Scholar 

  89. von Bergen TN, Blount MA (2012) Chronic use of chloroquine disrupts the urine concentration mechanism by lowering cAMP levels in the inner medulla. Am J Physiol Renal Physiol. doi:10.1152/ajprenal.00547.2011

  90. Wang X-Y, Beutler K, Nielsen J, Nielsen S, Knepper MA, Masilamani S (2002) Decreased abundance of collecting duct urea transporters UT-A1 and UT-A3 with ECF volume expansion. Am J Physiol Renal Physiol 282(4):F577–F584

    CAS  PubMed  Google Scholar 

  91. Wang Y, Klein JD, Blount MA, Martin CF, Kent KJ, Pech V, Wall SM, Sands JM (2009) Epac regulation of the UT-A1 urea transporter in rat IMCDs. J Am Soc Nephrol 20(3):2018–2024

    Article  CAS  PubMed  Google Scholar 

  92. Yang B, Bankir L, Gillespie A, Epstein CJ, Verkman AS (2002) Urea-selective concentrating defect in transgenic mice lacking urea transporter UT-B. J Biol Chem 277:10633–10637

    Article  CAS  PubMed  Google Scholar 

  93. Yang B, Verkman AS (2002) Analysis of double knockout mice lacking aquaporin-1 and urea transporter UT-B. J Biol Chem 277(39):36782–36786

    Article  CAS  PubMed  Google Scholar 

  94. Yano Y, Rodrigues AC Jr, deBraganca AC, Andrade LC, Magaldi AJ (2008) PKC stimulated by glucagon decreases UT-A1 urea transporter expression in rat IMCD. Pflugers Arch 456:1229–1237

    Article  CAS  PubMed  Google Scholar 

  95. Yao C, Anderson MO, Zhang J, Yang B, Phuan PW, Verkman AS (2012) Triazolothienopyrimidine inhibitors of urea transporter UT-B reduce urine concentration. J Am Soc Nephrol 23(7):1210–1220. doi:10.1681/ASN.2011070751

    Article  CAS  PubMed  Google Scholar 

  96. You G, Smith CP, Kanai Y, Lee W-S, Stelzner M, Hediger MA (1993) Cloning and characterization of the vasopressin-regulated urea transporter. Nature 365:844–847

    Article  CAS  PubMed  Google Scholar 

  97. Zhang C, Sands JM, Klein JD (2002) Vasopressin rapidly increases the phosphorylation of the UT-A1 urea transporter activity in rat IMCDs through PKA. Am J Physiol Renal Physiol 282(1):F85–F90

    CAS  PubMed  Google Scholar 

  98. Zhou L, Meng Y, Lei T, Zhao D, Su J, Zhao X, Yang B (2012) UT-B-deficient mice develop renal dysfunction and structural damage. BMC Nephrol 13:6. doi:10.1186/1471-2369-13-6

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This review was supported by NIH grants R01-DK41707, R01-DK89828, R21-DK91147 to JMS and JDK, and NIH grants K01-DK82733 and R03-DK91501 as well as Norman S. Coplon Extramural Grant, Satellite Healthcare to MAB.

Author information

Authors and Affiliations

  1. Renal Division, Department of Medicine, and Department of Physiology, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Janet D. Klein, Mitsi A. Blount & Jeff M. Sands

  2. Renal Division, Emory University School of Medicine, 1639 Pierce Drive, NE, WMB Room 338, Atlanta, GA, 30322, USA

    Jeff M. Sands

Authors
  1. Janet D. Klein
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mitsi A. Blount
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jeff M. Sands
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeff M. Sands.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Klein, J.D., Blount, M.A. & Sands, J.M. Molecular mechanisms of urea transport in health and disease. Pflugers Arch - Eur J Physiol 464, 561–572 (2012). https://doi.org/10.1007/s00424-012-1157-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-012-1157-0

Keywords

Search

Navigation