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Urea Transporters pp 79–107Cite as

Expression of Urea Transporters and Their Regulation

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Part of the book series: Subcellular Biochemistry ((SCBI,volume 73))

Abstract

UT-A and UT-B families of urea transporters consist of multiple isoforms that are subject to regulation of both acutely and by long-term measures. This chapter provides a brief overview of the expression of the urea transporter forms and their locations in the kidney. Rapid regulation of UT-A1 results from the combination of phosphorylation and membrane accumulation. Phosphorylation of UT-A1 has been linked to vasopressin and hyperosmolality, although through different kinases. Other acute influences on urea transporter activity are ubiquitination and glycosylation, both of which influence the membrane association of the urea transporter, again through different mechanisms. Long-term regulation of urea transport is most closely associated with the environment that the kidney experiences. Low-protein diets may influence the amount of urea transporter available. Conditions of osmotic diuresis, where urea concentrations are low, will prompt an increase in urea transporter abundance. Although adrenal steroids affect urea transporter abundance, conflicting reports make conclusions tenuous. Urea transporters are upregulated when P2Y2 purinergic receptors are decreased, suggesting a role for these receptors in UT regulation. Hypercalcemia and hypokalemia both cause urine concentration deficiencies. Urea transporter abundances are reduced in aging animals and animals with angiotensin-converting enzyme deficiencies. This chapter will provide information about both rapid and long-term regulation of urea transporters and provide an introduction into the literature.

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References

  1. Abdoun K, Stumpff F, Rabbani I, Martens H (2010) Modulation of urea transport across sheep rumen epithelium in vitro by SCFA and CO2. Am J Physiol Gastrointest Liver Physiol 298:G190–G202

    CAS  PubMed  Google Scholar 

  2. 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 Physiol 263:F24–F36

    CAS  Google Scholar 

  3. 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 Physiol 269:F225–F235

    CAS  Google Scholar 

  4. 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 55:5942–5950

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Artagaveytia N, Elalouf JM, De RC, Boivin R, Cirio A (2005) Expression of urea transporter (UT-A) mRNA in papilla and pelvic epithelium of kidney in normal and low protein fed sheep. Comp Biochem Physiol B: Biochem Mol Biol 140:279–285

    Google Scholar 

  6. Ashkar ZM, Martial S, Isozaki T, Price SR, Sands JM (1995) Urea transport in initial IMCD of rats fed a low-protein diet: functional properties and mRNA abundance. Am J Physiol Renal Physiol 268:F1218–F1223

    CAS  Google Scholar 

  7. Bagnasco SM, Peng T, Janech MG, Karakashian A, Sands JM (2001) Cloning and characterization of the human urea transporter UT-A1 and mapping of the human Slc14a2 gene. Am J Physiol Renal Physiol 281:F400–F406

    CAS  PubMed  Google Scholar 

  8. Bagnasco SM, Peng T, Nakayama Y, Sands JM (2000) Differential expression of individual UT-A urea transporter isoforms in rat kidney. J Am Soc Nephrol 11:1980–1986

    CAS  PubMed  Google Scholar 

  9. Bankir L (2001) Antidiuretic action of vasopressin: quantitative aspects and interaction between V1a and V2 receptor-mediated effects. Cardiovasc Res 51:372–390

    CAS  PubMed  Google Scholar 

  10. Bankir L, Chen K, Yang B (2004) Lack of UT-B in vasa recta and red blood cells prevents urea-induced improvement of urinary concentrating ability. Am J Physiol Renal Physiol 286:F144–F151

    CAS  PubMed  Google Scholar 

  11. Bansal AD, Hoffert JD, Pisitkun T, Hwang S, Chou CL, Boja ES, Wang G, Knepper MA (2010) Phosphoproteomic profiling reveals vasopressin-regulated phosphorylation sites in collecting duct. J Am Soc Nephrol 21:303–315

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Berl T (2000) On the adaptation of renal cells to hypertonicity. Am J of Kidney Dis 35:XLVII–XLVIL

    Google Scholar 

  13. 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:F1336–F1341

    CAS  PubMed Central  PubMed  Google Scholar 

  14. 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:F1308–F1313

    CAS  PubMed  Google Scholar 

  15. 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:F295–F299

    CAS  PubMed Central  PubMed  Google Scholar 

  16. 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

    CAS  PubMed Central  PubMed  Google Scholar 

  17. Bos JL (2003) Epac: a new cAMP target and new avenues in cAMP research. Nat Rev Mol Cell Biol 4:733–738

    CAS  PubMed  Google Scholar 

  18. Brooks HL, Ageloff S, Kwon TH, Brandt W, Terris JM, Seth A, Michea L, Nielsen S, Fenton R, Knepper MA (2003) cDNA array identification of genes regulated in rat renal medulla in response to vasopressin infusion. Am J Physiol Renal Physiol 284:F218–F228

    CAS  PubMed  Google Scholar 

  19. Cadnapaphornchai MA, Summer SN, Falk S, Thurman JM, Knepper MA, Schrier RW (2003) Effect of primary polydipsia on aquaporin and sodium transporter abundance. Am J Physiol Renal Physiol 285:F965–F971

    CAS  PubMed  Google Scholar 

  20. Chen G, Fröhlich O, Yang Y, Klein JD, Sands JM (2006) Loss of N-linked glycosylation reduces urea transporter UT-A1 response to vasopressin. J Biol Chem 281:27436–27442

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Chen G, Huang H, Fröhlich O, Yang Y, Klein JD, Price SR, Sands JM (2008) MDM2 E3 ubiquitin ligase mediates UT-A1 urea transporter ubiquitination and degradation. Am J Physiol Renal Physiol 295:F1528–F1534

    CAS  PubMed Central  PubMed  Google Scholar 

  23. 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 16:2864–2871

    CAS  PubMed  Google Scholar 

  24. Chou C-L, DiGiovanni SR, Luther A, Lolait SJ, Knepper MA (1995) Oxytocin as an antidiuretic hormone. II Role of V2 vasopressin receptor. Am J Physiol Renal Physiol 269:F78–F85

    CAS  Google Scholar 

  25. Chou C-L, DiGiovanni SR, Mejia R, Nielsen S, Knepper MA (1995) Oxytocin as an antidiuretic hormone. I. Concentration dependence of action. Am J Physiol Renal Physiol 269:F70–F77

    CAS  Google Scholar 

  26. Chou C-L, Knepper MA (1989) Inhibition of urea transport in inner medullary collecting duct by phloretin and urea analogues. Am J Physiol Renal Physiol 257:F359–F365

    CAS  Google Scholar 

  27. Chou C-L, Sands JM, Nonoguchi H, Knepper MA (1990) Urea-gradient associated fluid absorption with σurea = 1 in rat terminal collecting duct. Am J Physiol Renal Physiol 258:F1173–F1180

    CAS  Google Scholar 

  28. Cil O, Ertunc M, Onur R (2012) The diuretic effect of urea analog dimethylthiourea in female Wistar rats. Hum Exp Toxicol 31:1050–1055

    CAS  PubMed  Google Scholar 

  29. 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

    PubMed Central  PubMed  Google Scholar 

  30. Collins D, Winter DC, Hogan AM, Schirmer L, Baird AW, Stewart GS (2010) Differential protein abundance and function of UT-B transporters in human colon. Am J Physiol Gastrointest Liver Physiol 298:G345–G351

    CAS  PubMed Central  PubMed  Google Scholar 

  31. 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:F199–F208

    CAS  PubMed  Google Scholar 

  32. 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:F1123–F1131

    CAS  PubMed  Google Scholar 

  33. Cotte N, Balestre MN, Phalipou S, Hibert M, Manning M, Barberis C, Mouillac B (1998) Identification of residues responsible for the selective binding of peptide antagonists and agonists in the V2 vasopressin receptor. J Biol Chem 273:9462–29468

    Google Scholar 

  34. Dix L, Ward DT, Stewart GS (2013) Short communication: urea transporter protein UT-B in the bovine parotid gland. J Dairy Sci 96:1685–1690

    CAS  PubMed  Google Scholar 

  35. Doran JJ, Klein JD, Kim Y-H, Smith TD, Kozlowski SD, Gunn RB, Sands JM (2006) Tissue distribution of UT-A and UT-B mRNA and protein in rat. Am J Physiol Regul Integr Comp Physiol 290:R1446–R1459

    CAS  PubMed  Google Scholar 

  36. Esteva-Font C, Phuan P-W, Anderson MO, Verkman AS (2013) A small molecule screen identifies selective inhibitors of urea transporter UT-A. Chem Biol 20 (in press)

    Google Scholar 

  37. Esther CR Jr, Howard TE, Marino EM, Goddard JM, Capecchi MR, Bernstein KE (1996) Mice lacking angiotensin-converting enzyme have low blood pressure, renal pathology, and reduced male fertility. Lab Invest 74:953–965

    CAS  PubMed  Google Scholar 

  38. 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. J Clin Invest 99:2375–2385

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  40. Feng X, Huang H, Yang Y, Fröhlich O, Klein JD, Sands JM, Chen G (2009) Caveolin-1 directly interacts with UT-A1 urea transporter: the role of caveolae/lipid rafts in UT-A1 regulation at the cell membrane. Am J Physiol Renal Physiol 296:F1514–F1520

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Fenton RA, Cooper GJ, Morris ID, Smith CP (2002) Coordinated expression of UT-A and UT-B urea transporters in rat testis. Am J Physiol Cell Physiol 282:C1492–C1501

    CAS  PubMed  Google Scholar 

  42. Fenton RA, Cottingham CA, Stewart GS, Howorth A, Hewitt JA, Smith CP (2002) Structure and characterization of the mouse UT-A gene (Slc14a2). Am J Physiol Renal Physiol 282:F630–F638

    CAS  PubMed  Google Scholar 

  43. 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 16:1583–1592

    CAS  PubMed Central  PubMed  Google Scholar 

  44. Fenton RA, Hewitt JE, Howorth A, Cottingham CA, Smith CP (1999) The murine urea transporter genes Slc14a1 and Slc14a2 occur in tandem on chromosome 18. Cytogen Cell Gen 87:95–96

    CAS  Google Scholar 

  45. Fenton RA, Howorth A, Cooper GJ, Meccariello R, Morris ID, Smith CP (2000) Molecular characterization of a novel UT-A urea transporter isoform (UT-A5) in testis. Am J Physiol Cell Physiol 279:C1425–C1431

    CAS  PubMed  Google Scholar 

  46. Fenton RA, Stewart GS, Carpenter B, Howorth A, Potter EA, Cooper GJ, Smith CP (2002) Characterization of the mouse urea transporters UT-A1 and UT-A2. Am J Physiol Renal Physiol 283:F817–F825

    CAS  PubMed  Google Scholar 

  47. Fröhlich O, Klein JD, Smith PM, Sands JM, Gunn RB (2004) Urea transport in MDCK cells that are stably transfected with UT-A1. Am J Physiol Cell Physiol 286:C1264–C1270

    PubMed  Google Scholar 

  48. Fröhlich O, Klein JD, Smith PM, Sands JM, Gunn RB (2006) Regulation of UT-A1-mediated transepithelial urea flux in MDCK cells. Am J Physiol Cell Physiol 291:C600–C606

    PubMed  Google Scholar 

  49. Galla JH, Booker BB, Luke RG (1986) Role of the loop segment in the urinary concentrating defect of hypercalcemia. Kidney Int 29:977–982

    CAS  PubMed  Google Scholar 

  50. 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 15:558–565

    CAS  PubMed  Google Scholar 

  51. Geyer RR, Musa-Aziz R, Enkavi G, Mahinthichaichan P, Tajkhorshid E, Boron WF (2013) Movement of NH3 through the human urea transporter B: a new gas channel. Am J Physiol Renal Physiol 304:F1447–F1457

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Gillin AG, Sands JM (1992) Characteristics of osmolarity-stimulated urea transport in rat IMCD. Am J Physiol Renal Physiol 262:F1061–F1067

    CAS  Google Scholar 

  53. Gillin AG, Star RA, Sands JM (1993) Osmolarity-stimulated urea transport in rat terminal IMCD: role of intracellular calcium. Am J Physiol Renal Physiol 265:F272–F277

    CAS  Google Scholar 

  54. Guron G, Nilsson A, Nitescu N, Nielsen S, Sundelin B, Frokiaer J, Friberg P (1999) Mechanisms of impaired urinary concentrating ability in adult rats treated neonatally with enalapril. Acta Physiol Scand 165:103–112

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Helms MN, Chen X-J, Ramosevac S, Eaton DC, Jain L (2006) Dopamine regulation of amiloride-sensitive sodium channels in lung cells. Am J Physiol Lung Cell Mol Physiol 291:L610–L618

    CAS  PubMed  Google Scholar 

  57. Hoffert JD, Pisitkun T, Wang G, Shen RF, Knepper MA (2006) Quantitative phosphoproteomics of vasopressin-sensitive renal cells: regulation of aquaporin-2 phosphorylation at two sites. Proc Natl Acad Sci USA 103:7159–7164

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Honegger KJ, Capuano P, Winter C, Bacic D, Stange G, Wagner CA, Biber J, Murer H, Hernando N (2006) Regulation of sodium-proton exchanger isoform 3 (NHE3) by PKA and exchange protein directly activated by cAMP (EPAC). Proc Natl Acad Sci USA 103:803–808

    CAS  PubMed Central  PubMed  Google Scholar 

  59. Hoorn EJ, Hoffert JD, Knepper MA (2005) Combined proteomics and pathways analysis of collecting duct reveals a protein regulatory network activated in vasopressin escape. J Am Soc Nephrol 16:2852–2863

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Hu MC, Bankir L, Michelet S, Rousselet G, Trinh-Trang-Tan M-M (2000) Massive reduction of urea transporters in remnant kidney and brain of uremic rats. Kidney Int 58:1202–1210

    CAS  PubMed  Google Scholar 

  61. Hu MC, Bankir L, Trinh-Trang-Tan MM (1999) mRNA expression of renal urea transporters in normal and Brattleboro rats: effect of dietary protein intake. Exp Nephrol 7:44–51

    CAS  PubMed  Google Scholar 

  62. Huang H, Feng X, Zhuang J, Froehlich O, Klein JD, Cai H, Sands JM, Chen G (2010) Internalization of UT-A1 urea transporter is dynamin dependent and mediated by both caveolae and clathrin coated pit pathways. Am J Physiol Renal Physiol 299:F1389–F1395

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Hwang S, Gunaratne R, Rinschen MM, Yu M-J, Pisitkun T, Hoffert JD, Fenton RA, Knepper MA, Chou C-L (2010) Vasporessin increases phosphorylation of ser84 and ser486 in Slc14a2 collecting duct urea transporters. Am J Physiol Renal Physiol 299:F559–F567

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Igarashi P, Whyte DA, Nagami GT (1996) Cloning and kidney cell-specific activity of the promoter of the murine renal Na-K-Cl cotransporter gene. J Biol Chem 271:9666–9674

    CAS  PubMed  Google Scholar 

  65. Ilori TO, Blount MA, Martin CF, Sands JM, Klein JD (2013) Urine concentration in the diabetic mouse requires both water and urea transporters. Am J Physiol Renal Physiol 304:F103–F111

    CAS  PubMed Central  PubMed  Google Scholar 

  66. 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

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Inoue H, Jackson SD, Vikulina T, Klein JD, Tomita K, Bagnasco SM (2004) Identification and characterization of a Kidd antigen/UT-B urea transporter expressed in human colon. Am J Physiol Cell Physiol 287:C30–C35

    CAS  PubMed  Google Scholar 

  68. Inoue T, Terris J, Ecelbarger CA, Chou C-L, Nielsen S, Knepper MA (1999) Vasopressin regulates apical targeting of aquaporin-2 but not of UT1 urea transporter in renal collecting duct. Am J Physiol 276:F559–F566

    CAS  PubMed  Google Scholar 

  69. 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 

  70. Isozaki T, Verlander JW, Sands JM (1993) Low protein diet alters urea transport and cell structure in rat initial inner medullary collecting duct. J Clin Invest 92:2448–2457

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Issa VS, Andrade L, Ayub-Ferreira SM, Bacal F, de Bragança AC, Guimarães GV, Marcondes-Braga FG, Cruz FD, Chizzola PR, Conceição-Souza GE, Velasco IT, Bocchi EA (2013) Hypertonic saline solution for prevention of renal dysfunction in patients with decompensated heart failure. Int J Cardiol 167:34–40

    PubMed  Google Scholar 

  72. Ito M, Oliverio MI, Mannon PJ, Best CF, Maeda N, Smithies O, Coffman TM (1995) Regulation of blood pressure by the type 1A angiotensin II receptor gene. Proc Natl Acad Sci USA 92:3521–3525

    CAS  PubMed Central  PubMed  Google Scholar 

  73. 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

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Jeon US, Han K-H, Park S-H, Lee SD, Sheen MR, Jung J-Y, Kim WY, Sands JM, Kim J, Kwon HM (2007) Downregulation of renal TonEBP in hypokalemic rats. Am J Physiol Renal Physiol 293:F408–F415

    CAS  PubMed  Google Scholar 

  75. Jeon US, Kim JA, Sheen MR, Kwon HM (2006) How tonicity regulates genes: story of TonEBP transcriptional activator. Acta Physiol Scand 187:241–247

    CAS  Google Scholar 

  76. Jin W, Yao X, Wang T, Ji Q, Li Y, Yang X, Yao L (2012) Effects of hyperosmolality on expression of urea transporter A2 and aquaporin 2 in mouse medullary collecting duct cells. J Huazhong Univ Sci Technol [Med Sci] 32:59–64

    CAS  Google Scholar 

  77. Jung J-Y, Madsen KM, Han K-H, Yang C-W, Knepper MA, Sands JM, Kim J (2003) Expression of urea transporters in potassium-depleted mouse kidney. Am J Physiol Renal Physiol 285:F1210–F1224

    CAS  PubMed  Google Scholar 

  78. Kakinuma Y, Fogo A, Inagami T, Ichikawa I (1993) Intrarenal localization of angiotensin II type 1 receptor mRNA in the rat. Kidney Int 43:1229–1235

    CAS  PubMed  Google Scholar 

  79. 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

    CAS  Google Scholar 

  80. Karakashian A, Timmer RT, Klein JD, Gunn RB, Sands JM, Bagnasco SM (1999) Cloning and characterization of two new mRNA isoforms of the rat renal urea transporter: UT-A3 and UT-A4. J Am Soc Nephrol 10:230–237

    CAS  PubMed  Google Scholar 

  81. Kato A, Klein JD, Zhang C, Sands JM (2000) Angiotensin II increases vasopressin-stimulated facilitated urea permeability in rat terminal IMCDs. Am J Physiol Renal Physiol 279:F835–F840

    CAS  PubMed  Google Scholar 

  82. Kato A, Naruse M, Knepper MA, Sands JM (1998) Long-term regulation of inner medullary collecting duct urea transport in rat. J Am Soc Nephrol 9:737–745

    CAS  PubMed  Google Scholar 

  83. Kato A, Sands JM (1999) Urea transport processes are induced in rat IMCD subsegments when urine concentrating ability is reduced. Am J Physiol Renal Physiol 276:F62–F71

    CAS  Google Scholar 

  84. Kihara M, Umemura S, Sumida Y, Yokoyama N, Yabana M, Nyui N, Tamura K, Murakami K, Fukamizu A, Ishii M (1998) Genetic deficiency of angiotensinogen produces an impaired urine concentrating ability in mice. Kidney Int 53:548–555

    CAS  PubMed  Google Scholar 

  85. Kim D-U, Klein JD, Racine S, Murrell BP, Sands JM (2005) Urea may regulate urea transporter protein abundance during osmotic diuresis. Am J Physiol Renal Physiol 288:F188–F197

    CAS  PubMed  Google Scholar 

  86. 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:F303–F309

    CAS  PubMed  Google Scholar 

  87. 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

    CAS  PubMed  Google Scholar 

  88. Kim Y-H, Kim D-U, Han K-H, Jung J-Y, Sands JM, Knepper MA, Madsen KM, Kim J (2002) Expression of urea transporters in the developing rat kidney. Am J Physiol Renal Physiol 282:F530–F540

    CAS  PubMed  Google Scholar 

  89. Kim YM, Kim WY, Lee HW, Kim J, Kwon HM, Klein JD, Sands JM, Kim D (2009) Urea and NaCl regulate UT-A1 urea transporter in opposing directions via TonEBP pathway during osmotic diuresis. Am J Physiol Renal Physiol 296:F67–F77

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Kiran D, Mutsvangwa T (2010) Effects of partial ruminal defaunation on urea-nitrogen recycling, nitrogen metabolism, and microbial nitrogen supply in growing lambs fed low or high dietary crude protein concentrations. J Anim Sci 88:1034–1047

    CAS  PubMed  Google Scholar 

  91. Klein JD, Blount MA, Fröhlich O, Denson C, Tan X, Sim J, Martin CF, Sands JM (2010) Phosphorylation of UT-A1 on serine 486 correlates with membrane accumulation and urea transport activity in both rat IMCDs and cultured cells. Am J Physiol Renal Physiol 298:F935–F940

    CAS  PubMed Central  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  93. Klein JD, Froehlich O, Mistry AC, Kent KJ, Martin CF, Sands JM (2013) Transgenic mice expressing UT-A1, but lacking UT-A3, have intact urine concentrating ability. FASEB J 27(1111):17

    Google Scholar 

  94. 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

    CAS  PubMed  Google Scholar 

  95. 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. Am J Physiol Renal Physiol 302:F1098–F1103

    CAS  PubMed Central  PubMed  Google Scholar 

  96. 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:F517–F524

    CAS  PubMed  Google Scholar 

  97. 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

    CAS  PubMed  Google Scholar 

  98. 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 

  99. Knepper MA, Miranda CA (2013) Urea channel inhibitors: a new functional class of aquaretics. Kidney Int 83:991–993

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Knepper MA, Sands JM, Chou C-L (1989) Independence of urea and water transport in rat inner medullary collecting duct. Am J Physiol Renal Physiol 256:F610–F621

    CAS  Google Scholar 

  101. Knox FG, Burnett JC Jr, Kohan DE, Spielman WS, Strand JC (1980) Escape from the sodium-retaining effects of mineralocorticoids. Kidney Int 17:263–276

    CAS  PubMed  Google Scholar 

  102. Kondo Y, Imai M (1987) Effects of glutaraldehyde fixation on renal tubular function. I. Preservation of vasopressin-stimulated water and urea pathways in rat papillary collecting duct. Pfluegers Arch 408:479–483

    CAS  Google Scholar 

  103. Kudo LH, César KR, Ping WC, Rocha AS (1992) Effect of peritubular hypertonicity on water and urea transport of inner medullary collecting duct. Am J Physiol Renal, Fluid Electrolyte Physiol 262:F338–F347

    CAS  Google Scholar 

  104. Kudo LH, Van Baak AA, Rocha AS (1990) Effect of vasopressin on sodium transport across inner medullary collecting duct. Am J Physiol Renal Physiol 258:F1438–F1447

    CAS  Google Scholar 

  105. Kwun Y-S, Yeo SW, Ahn Y-H, Lim S-W, Jung J-Y, Kim W-Y, Sands JM, Kim J (2003) Immunohistochemical localization of urea transporters A and B in the rat cochlea. Hearing Res 183:84–96

    CAS  Google Scholar 

  106. Lam AK, Ko BC, Tam S, Morris R, Yang JY, Chung SK, Chung SS (2004) Osmotic response element-binding protein (OREBP) is an essential regulator of the urine concentrating mechanism. J Biol Chem 279:48048–48054

    CAS  PubMed  Google Scholar 

  107. Laroche-Joubert N, Marsy S, Michelet S, Imbert-Teboul M, Doucet A (2002) Protein kinase A-independent activation of ERK and H, K-ATPase by cAMP in native kidney cells. Role of Epac I. J Biol Chem 277:18598–18604

    CAS  PubMed  Google Scholar 

  108. Leroy C, Basset G, Gruel G, Ripoche P, Trinh-Trang-Tan M-M, Rousselet G (2000) Hyperosmotic NaCl and urea synergistically regulate the expression of the UT-A2 urea transporter in vitro and in vivo. Biochem Biophys Res Commun 271:368–373

    CAS  PubMed  Google Scholar 

  109. Levi M, Peterson L, Berl T (1983) Mechanism of concentrating defect in hypercalcemia. Role of polydipsia and prostaglandins. Kidney Int 23:489–497

    CAS  PubMed  Google Scholar 

  110. 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:F1154–F1162

    CAS  PubMed  Google Scholar 

  111. 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 19:1975–1981

    CAS  PubMed Central  PubMed  Google Scholar 

  112. Li F, Lei T, Zhu J, Wang W, Sun Y, Chen J, Dong Z, Zhou H, Yang B (2013) A novel small-molecule thienoquinolin urea transporter inhibitor acts as a potential diuretic. Kidney Int 83:1076–1086

    CAS  PubMed  Google Scholar 

  113. Li Y, Konings IBM, Zhao J, Price LS, de Heer E, Deen PMT (2008) Renal expression of exchange protein directly activated by cAMP (Epac) 1 and 2. Am J Physiol Renal Physiol 295:F525–F533

    CAS  PubMed  Google Scholar 

  114. 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:R479–R492

    CAS  PubMed  Google Scholar 

  115. Lucien N, Bruneval P, Lasbennes F, Belair MF, Mandet C, Cartron JP, Bailly P, Trinh-Trang-Tan MM (2005) UT-B1 urea transporter is expressed along the urinary and gastrointestinal tracts of the mouse. Am J Physiol Regul Integr Comp Physiol 288:R1046–R1056

    CAS  PubMed  Google Scholar 

  116. Ludden PA, Stohrer RM, Austin KJ, Atkinson RL, Belden EL, Harlow HJ (2009) Effect of protein supplementation on expression and distribution of urea transporter-B in lambs fed low-quality forage. J Anim Sci 87:1354–1365

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  118. Magaldi AJ, Cesar KR, Yano Y (1994) Effect of insulin on water and urea transport in the inner medullary collecting duct. Am J Physiol Renal Physiol 266:F394–F399

    CAS  Google Scholar 

  119. Marini JC, Klein JD, Sands JM, Van Amburgh ME (2004) Effect of nitrogen intake on nitrogen recycling and urea transporter abundance in lambs. J Anim Sci 82:1157–1164

    CAS  PubMed  Google Scholar 

  120. Meng Y, Zhao C, Zhang X, Zhao H, Guo L, Lu B, Zhao X, Yang B (2009) Surface electrocardiogram and action potential in mice lacking urea transporter UT-B. Sci China C Life Sci 52:474–478

    CAS  PubMed  Google Scholar 

  121. Mistry AC, Mallick R, Fröhlich O, Klein JD, Rehm A, Chen G, Sands JM (2007) The UT-A1 urea transporter interacts with snapin, a snare-associated protein. J Biol Chem 282:30097–30106

    CAS  PubMed  Google Scholar 

  122. Mistry AC, Mallick R, Klein JD, Sands JM, Froehlich O (2010) Functional characterization of the central hydrophilic linker region of the urea transporter UT-A1: cAMP activation and snapin binding. Am J Physiol Cell Physiol 298:C1431–C1437

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Morgan T, Berliner RW (1968) Permeability of the loop of Henle, vasa recta, and collecting duct to water, urea, and sodium. Am J Physiol 215:108–115

    CAS  PubMed  Google Scholar 

  124. Morgan T, Sakai F, Berliner RW (1968) In vitro permeability of medullary collecting duct to water and urea. Am J Physiol 214:574–581

    CAS  PubMed  Google Scholar 

  125. Morris RG, Uchida S, Brooks H, Knepper MA, Chou CL (2005) Altered expression profile of transporters in the inner medullary collecting duct of aquaporin-1 knockout mice. Am J Physiol Renal Physiol 289:F194–F199

    CAS  PubMed  Google Scholar 

  126. Mujais SK, Kauffman S, Katz AI (1986) Angiotensin II binding sites in individual segments of the rat nephron. J Clin Invest 77:315–318

    CAS  PubMed Central  PubMed  Google Scholar 

  127. Nakayama Y, Naruse M, Karakashian A, Peng T, Sands JM, Bagnasco SM (2001) Cloning of the rat Slc14a2 gene and genomic organization of the UT-A urea transporter. Biochim Biophys Acta 1518:19–26

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  129. 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. J Am Soc Nephrol 8:517–523

    CAS  PubMed  Google Scholar 

  130. Nielsen S, DiGiovanni SR, Christensen EI, Knepper MA, Harris HW (1993) Cellular and subcellular immunolocalization of vasopressin-regulated water channel in rat kidney. Proc Natl Acad Sci USA 90:11663–11667

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Nielsen S, Knepper MA (1993) Vasopressin activates collecting duct urea transporters and water channels by distinct physical processes. Am J Physiol Renal Physiol 265:F204–F213

    CAS  Google Scholar 

  132. Nielsen S, Terris J, Smith CP, Hediger MA, Ecelbarger CA, Knepper MA (1996) Cellular and subcellular localization of the vasopressin-regulated urea transporter in rat kidney. Proc Natl Acad Sci USA 93:5495–5500

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Nonoguchi H, Sands JM, Knepper MA (1988) Atrial natriuretic factor inhibits vasopressin-stimulated osmotic water permeability in rat inner medullary collecting duct. J Clin Invest 82:1383–1390

    CAS  PubMed Central  PubMed  Google Scholar 

  134. Okubo S, Niimura F, Matsusaka T, Fogo A, Hogan BLM, Ichikawa I (1998) Angiotensinogen gene null-mutant mice lack homeostatic regulation of glomerular filtration and tubular reabsorption. Kidney Int 53:617–625

    CAS  PubMed  Google Scholar 

  135. Pallone T, Zhang Z, Rhinehart K (2003) Physiology of the renal medullary microcirculation. Am J Physiol Renal Physiol 284:F253–F266

    CAS  PubMed  Google Scholar 

  136. Pannabecker TL, Dantzler WH, Layton HE, Layton AT (2008) Role of three-dimensional architecture in the urine concentrating mechanism of the rat renal inner medulla. Am J Physiol Renal Physiol 295:F1271–F1285

    CAS  PubMed Central  PubMed  Google Scholar 

  137. Peil AE, Stolte H, Schmidt-Nielsen B (1990) Uncoupling of glomerular and tubular regulations of urea excretion in rat. Am J Physiol Renal Physiol 258:F1666–F1674

    CAS  Google Scholar 

  138. 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:F853–F858

    CAS  PubMed  Google Scholar 

  139. Potter EA, Stewart G, Smith CP (2006) Urea flux across MDCK-mUT-A2 monolayers is acutely sensitive to AVP, cAMP, and [Ca2+]i. Am J Physiol Renal Physiol 291:F122–F128

    CAS  PubMed  Google Scholar 

  140. 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:F144–F152

    CAS  PubMed  Google Scholar 

  141. 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 9:1359–1366

    CAS  PubMed  Google Scholar 

  142. Promeneur D, Rousselet G, Bankir L, Bailly P, Cartron JP, Ripoche P, Trinh-Trang-Tan MM (1996) Evidence for distinct vascular and tubular urea transporters in the rat kidney. J Am Soc Nephrol 7:852–860

    CAS  PubMed  Google Scholar 

  143. Rocha AS, Ping WC, Kudo LH (1991) Effect of chlorpropamide on water and urea transport in the inner medullary collecting duct. Kidney Int 39:79–86

    CAS  PubMed  Google Scholar 

  144. Rouch AJ, Kudo LH (1996) α2-Adrenergic-mediated inhibition of water and urea permeability in the rat IMCD. Am J Physiol Renal Physiol 271:F150–F157

    CAS  Google Scholar 

  145. 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:F216–F225

    CAS  PubMed  Google Scholar 

  146. Sands JM (1999) Regulation of renal urea transporters. J Am Soc Nephrol 10:635–646

    CAS  PubMed  Google Scholar 

  147. Sands JM (2003) Urine-concentrating ability in the aging kidney. Sci Aging Knowledge Environ 24:pe15

    Google Scholar 

  148. Sands JM (2009) Urinary concentration and dilution in the aging kidney. Semin Nephrol 29:579–586

    CAS  PubMed Central  PubMed  Google Scholar 

  149. Sands JM (2012) Urine concentrating and diluting ability during aging. J Gerontol A Biol Sci Med Sci 67:1352–1357

    PubMed Central  PubMed  Google Scholar 

  150. Sands Jeff M (2013) Urea transporter inhibitors: en route to new diuretics. Chem Biol 20:1201–1202

    CAS  PubMed  Google Scholar 

  151. Sands JM, Blount MA, Klein JD (2011) Regulation of renal urea transport by vasopressin. Trans Am Clin Climatol Assoc 122:82–92

    PubMed Central  PubMed  Google Scholar 

  152. Sands JM, Flores FX, Kato A, Baum MA, Brown EM, Ward DT, Hebert SC, Harris HW (1998) Vasopressin-elicited water and urea permeabilities are altered in the inner medullary collecting duct in hypercalcemic rats. Am J Physiol Renal Physiol 274:F978–F985

    CAS  Google Scholar 

  153. Sands JM, Knepper MA (1987) Urea permeability of mammalian inner medullary collecting duct system and papillary surface epithelium. J Clin Invest 79:138–147

    CAS  PubMed Central  PubMed  Google Scholar 

  154. Sands JM, Naruse M, Baum M, Jo I, Hebert SC, Brown EM, Harris HW (1997) Apical extracellular calcium/polyvalent cation-sensing receptor regulates vasopressin-elicited water permeability in rat kidney inner medullary collecting duct. J Clin Invest 99:1399–1405

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  156. Sands JM, Schrader DC (1991) An independent effect of osmolality on urea transport in rat terminal IMCDs. J Clin Invest 88:137–142

    CAS  PubMed Central  PubMed  Google Scholar 

  157. Sasaki A, Kida O, Kita T, Kato J, Nakamura S, Kodama K, Miyata A, Kangawa K, Matsuo H, Tanaka K (1989) Effects of antiserum against α-rat atrial natriuretic polypeptide in spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 257:H1104–H1109

    CAS  Google Scholar 

  158. Schmidt C, Hocherl K, Bucher M (2007) Cytokine-mediated regulation of urea transporters during experimental endotoxemia. Am J Physiol Renal Physiol 292:F1479–F1489

    CAS  PubMed  Google Scholar 

  159. 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

    CAS  PubMed Central  PubMed  Google Scholar 

  160. Seamon KB, Padgett W, Daly JW (1981) Forskolin—unique diterpene activator of adenylate cyclase in membranes and intact cells. Proc Natl Acad Sci USA 87:3363–3367

    Google Scholar 

  161. Shayakul C, Knepper MA, Smith CP, DiGiovanni SR, Hediger MA (1997) Segmental localization of urea transporter mRNAs in rat kidney. Am J Physiol 272:F654–F660

    CAS  PubMed  Google Scholar 

  162. Shayakul C, Smith CP, Mackenzie HS, Lee W-S, Brown D, Hediger MA (2000) Long-term regulation of urea transporter expression by vasopressin in Brattleboro rats. Am J Physiol Renal Physiol 278:F620–F627

    CAS  PubMed  Google Scholar 

  163. Shayakul C, Steel A, Hediger MA (1996) Molecular cloning and characterization of the vasopressin-regulated urea transporter of rat kidney collecting ducts. J Clin Invest 98:2580–2587

    CAS  PubMed Central  PubMed  Google Scholar 

  164. Shayakul C, Tsukaguchi H, Berger UV, Hediger MA (2001) Molecular characterization of a novel urea transporter from kidney inner medullary collecting ducts. Am J Physiol Renal Physiol 280:F487–F494

    CAS  PubMed  Google Scholar 

  165. Shimizu MHM, Volpini RA, de Bragança AC, Campos R, Canale D, Sanches TR, Andrade L, Seguro AC (2013) N-acetylcysteine attenuates renal alterations induced by senescence in the rat. Exp Gerontol 48:298–303

    CAS  PubMed  Google Scholar 

  166. Simmons NL, Chaudhry AS, Graham C, Scriven ES, Thistlethwaite A, Smith CP, Stewart GS (2009) Dietary regulation of ruminal bovine UT-B urea transporter expression and localization. J Anim Sci 87:3288–3299

    CAS  PubMed  Google Scholar 

  167. Smith CP, Lee W-S, Martial S, Knepper MA, You G, Sands JM, Hediger MA (1995) Cloning and regulation of expression of the rat kidney urea transporter (rUT2). J Clin Invest 96:1556–1563

    CAS  PubMed Central  PubMed  Google Scholar 

  168. 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:C1087–C1093

    CAS  PubMed  Google Scholar 

  169. Spector DA, Yang Q, Liu J, Wade JB (2004) Expression, localization, and regulation of urea transporter B in rat urothelia. Am J Physiol Renal Physiol 287:F102–F108

    CAS  PubMed  Google Scholar 

  170. Star RA (1990) Apical membrane limits urea permeation across the rat inner medullary collecting duct. J Clin Invest 86:1172–1178

    CAS  PubMed Central  PubMed  Google Scholar 

  171. Star RA, Nonoguchi H, Balaban R, Knepper MA (1988) Calcium and cyclic adenosine monophosphate as second messengers for vasopressin in the rat inner medullary collecting duct. J Clin Invest 81:1879–1888

    CAS  PubMed Central  PubMed  Google Scholar 

  172. Starke S, Muscher AS, Hirschhausen N, Pfeffer E, Breves G, Huber K (2012) Expression of urea transporters is affected by dietary nitrogen restriction in goat kidney. J Anim Sci 90:3889–3897

    CAS  PubMed  Google Scholar 

  173. Stewart GS, Graham C, Cattell S, Smith TPL, Simmons NL, Smith CP (2005) UT-B is expressed in bovine rumen: potential role in ruminal urea transport. Am J Physiol Regul Integr Comp Physiol 289:R605–R612

    CAS  PubMed  Google Scholar 

  174. Stewart GS, King SL, Potter EA, Smith CP (2007) Acute regulation of the urea transporter mUT-A3 expressed in a MDCK cell line. Am J Physiol Renal Physiol 292:F1157–F1163

    CAS  PubMed  Google Scholar 

  175. Stewart GS, O’Brien JH, Smith CP (2008) Ubiquitination regulates the plasma membrane expression of renal UT-A urea transporters. Am J Physiol Cell Physiol 295:C121–C129

    CAS  PubMed  Google Scholar 

  176. Stewart GS, Thistlethwaite A, Lees H, Cooper GJ, Smith C (2009) Vasopressin regulation of the renal UT-A3 urea transporter. Am J Physiol Renal Physiol 296:F642–F649

    CAS  PubMed  Google Scholar 

  177. 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:F201–F208

    CAS  PubMed Central  PubMed  Google Scholar 

  178. Su H, Carter CB, Laur O, Sands JM, Chen G (2012) Forskolin stimulation promotes urea transporter UT-A1 ubiquitination, endocytosis, and degradation in MDCK cells. Am J Physiol Renal Physiol 303:F1325–F1332

    CAS  PubMed Central  PubMed  Google Scholar 

  179. Su H, Liu B, Frohlich O, Ma H, Sands JM, Chen G (2013) Small GTPase Rab14 down-regulates UT-A1 urea transport activity through enhanced clathrin-dependent endocytosis. FASEB J 27:4100–4107

    CAS  PubMed Central  PubMed  Google Scholar 

  180. Terada Y, Tomita K, Nonoguchi H, Marumo F (1993) PCR localization of angiotensin II receptor and angiotensin mRNAs in rat kidney. Kidney Int 43:1251–1259

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  182. Terris JM, Knepper MA, Wade JB (2001) UT-A3: localization and characterization of an additional urea transporter isoform in the IMCD. Am J Physiol Renal Physiol 280:F325–F332

    CAS  PubMed  Google Scholar 

  183. 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:F37–F44

    CAS  PubMed Central  PubMed  Google Scholar 

  184. Tian W, Cohen DM (2001) Signaling and gene regulation by urea in cells of the mammalian kidney medulla. Comp Biochem Physiol A: Mol Integr Physiol 130:429–436

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  186. Timmer RT, Klein JD, Bagnasco SM, Doran JJ, Verlander JW, Gunn RB, Sands JM (2001) Localization of the urea transporter UT-B protein in human and rat erythrocytes and tissues. Am J Physiol Cell Physiol 281:C1318–C1325

    CAS  PubMed  Google Scholar 

  187. Trinh-Trang-Tan M-M, Cartron JP, Bankir L (2005) Molecular basis for the dialysis disequilibrium syndrome: altered aquaporin and urea transporter expression in the brain. Nephrol Dial Transplant 20:1984–1988

    CAS  PubMed  Google Scholar 

  188. 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:F912–F922

    PubMed  Google Scholar 

  189. 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:R1355–R1365

    CAS  PubMed  Google Scholar 

  190. Uawithya P, Pisitkun T, Ruttenberg BE, Knepper MA (2008) Transcriptional profiling of native inner medullary collecting duct cells from rat kidney. Physiol Genomics 32:229–253

    CAS  PubMed Central  PubMed  Google Scholar 

  191. Verkman AS, Yang BX, Song YL, Manley GT, Ma TH (2000) Role of water channels in fluid transport studied by phenotype analysis of aquaporin knockout mice. Exp Physiol 85:233S–241S

    CAS  PubMed  Google Scholar 

  192. 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 303:F900–F905

    Google Scholar 

  193. Wade JB, Lee AJ, Liu J, Ecelbarger CA, Mitchell C, Bradford AD, Terris J, Kim G-H, Knepper MA (2000) UT-A2: a 55 kDa urea transporter protein in thin descending limb of Henle’s loop whose abundance is regulated by vasopressin. Am J Physiol Renal Physiol 278:F52–F62

    CAS  PubMed  Google Scholar 

  194. Wagner L, Klein JD, Sands JM, Baylis C (2002) Urea transporters are widely distributed in endothelial cells and mediate inhibition of L-arginine transport. Am J Physiol Renal Physiol 283:F578–F582

    CAS  PubMed Central  PubMed  Google Scholar 

  195. Wall SM, Suk Han J, Chou C-L, Knepper MA (1992) Kinetics of urea and water permeability activation by vasopressin in rat terminal IMCD. Am J Physiol Renal Physiol 262:F989–F998

    CAS  Google Scholar 

  196. 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:F577–F584

    CAS  PubMed  Google Scholar 

  197. Wang X, Harris PC, Somlo S, Batlle D, Torres VE (2009) Effect of calcium-sensing receptor activation in models of autosomal recessive or dominant polycystic kidney disease. Nephrol Dial Transplant 24:526–534

    CAS  PubMed Central  PubMed  Google Scholar 

  198. 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 20:2018–2024

    CAS  PubMed Central  PubMed  Google Scholar 

  199. Wang Y, Klein JD, Fröhlich O, Sands JM (2013) Role of protein kinase C-a in hypertonicity-stimulated urea permeability in mouse inner medullary collecting ducts. Am J Physiol Renal Physiol 304:F233–F238

    CAS  PubMed Central  PubMed  Google Scholar 

  200. Wang Y, Liedtke CM, Klein JD, Sands JM (2010) Protein kinase C regulates urea permeability in the rat inner medullary collecting duct. Am J Physiol Renal Physiol 299:F1401–F1406

    CAS  PubMed Central  PubMed  Google Scholar 

  201. Xu Y, Olives B, Bailly P, Fischer E, Ripoche P, Ronco P, Cartron J-P, Rondeau E (1997) Endothelial cells of the kidney vasa recta express the urea transporter HUT11. Kidney Int 51:138–146

    CAS  PubMed  Google Scholar 

  202. Yamaguchi Y, Takaki S, Hyodo S (2009) Subcellular distribution of urea transporter in the collecting tubule of shark kidney is dependent on environmental salinity. J Exp Zool Part A Ecol Genet Physiol 311:705–718

    Google Scholar 

  203. 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

    CAS  PubMed  Google Scholar 

  204. Yang JY, Tam WY, Tam S, Guo H, Wu X, Li G, Chau JFL, Klein JD, Chung SK, Sands JM, Chung SS (2006) Genetic restoration of aldose reductase to the collecting tubules restores maturation of the urine concentrating mechanism. Am J Physiol Renal Physiol 291:F186–F195

    CAS  PubMed  Google Scholar 

  205. S-k Yang, Xiao L, Li J, Liu F, Sun L, Kanwar YS (2013) Role of guanine-nucleotide exchange factor Epac in renal physiology and pathophysiology. Am J Physiol Renal Physiol 304:F831–F839

    Google Scholar 

  206. Yano Y, Monteiro JL, Seguro AC (1994) Effect of amphotericin B on water and urea transport in the inner medullary collecting duct. J Am Soc Nephrol 5:68–74

    CAS  PubMed  Google Scholar 

  207. 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

    CAS  PubMed  Google Scholar 

  208. 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 23:1210–1220

    CAS  PubMed Central  PubMed  Google Scholar 

  209. Yasui M, Zelenin SM, Celsi G, Aperia A (1997) Adenylate cyclase-coupled vasopressin receptor activates AQP2 promoter via a dual effect on CRE and AP1 elements. Am J Physiol Renal Physiol 272:F443–F450

    CAS  Google Scholar 

  210. Yip KP (2008) Epac-mediated Ca2+ mobilization and exocytosis in inner medullary collecting duct. Am J Physiol Renal Physiol 291:F882–F890

    Google Scholar 

  211. 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

    CAS  PubMed  Google Scholar 

  212. Yu H, Meng Y, Wang LS, Jin X, Gao LF, Zhou L, Ji K, Li Y, Zhao LJ, Chen GQ, Zhao XJ, Yang B (2009) Differential protein expression in heart in UT-B null mice with cardiac conduction defects. Proteomics 9:504–511

    CAS  PubMed  Google Scholar 

  213. Yu MJ, Pisitkun T, Wang G, Aranda JF, Gonzales PA, Tchapyjnikov D, Shen RF, Alonso MA, Knepper MA (2008) Large-scale quantitative LC-MS/MS analysis of detergent-resistant membrane proteins from rat renal collecting duct. Am J Physiol Cell Physiol 295:C661–C678

    CAS  PubMed Central  PubMed  Google Scholar 

  214. Yu MJ, Pisitkun T, Wang G, Shen RF, Knepper MA (2006) LC-MS/MS analysis of apical and basolateral plasma membranes of rat renal collecting duct cells. Mol Cell Proteom 5:2131–2145

    CAS  Google Scholar 

  215. 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:F85–F90

    CAS  PubMed  Google Scholar 

  216. Zhang Y, Sands JM, Kohan DE, Nelson RD, Martin CF, Carlson NG, Kamerath CD, Ge Y, Klein JD, Kishore BK (2008) Potential role of purinergic signaling in urinary concentration in inner medulla: insights from P2Y2 receptor gene knockout mice. Am J Physiol Renal Physiol 295:F1715–F1724

    CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

This work was supported by NIH grants R01-DK89828 and R21-DK91147.

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  1. Renal Division, Department of Medicine and Department of Physiology, Emory University School of Medicine, WMB Room 3319B, 1639 Pierce Drive, NE, Atlanta, GA, 30322, USA

    Janet D. Klein

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  1. School of Basic Medical Sciences, Department of Pharmacology, Peking University, Beijing, China

    Baoxue Yang

  2. Renal Division, Department of Medicine and Department of Physiology, Emory University School of Medicine, Atlanta, Georgia, USA

    Jeff M. Sands

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Klein, J.D. (2014). Expression of Urea Transporters and Their Regulation. In: Yang, B., Sands, J. (eds) Urea Transporters. Subcellular Biochemistry, vol 73. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9343-8_6

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