Advertisement

The Physiology of Water Homeostasis

  • Jeff M. SandsEmail author
  • David B. Mount
  • Harold E. Layton
Chapter

Abstract

Water is the most abundant constituent in the body. Vasopressin secretion, water ingestion, and the renal concentrating mechanism collaborate to maintain human body fluid osmolality nearly constant. Abnormalities in these processes cause hyponatremia, hypernatremia, and polyuria. The primary hormonal control of renal water excretion is by vasopressin (also named antidiuretic hormone). Thirst and vasopressin release from the posterior pituitary are under the control of osmoreceptive neurons in the central nervous system. The kidney maintains blood plasma osmolality and sodium concentration nearly constant by means of mechanisms that independently regulate water and sodium excretion. The renal medulla produces concentrated urine through the generation of an osmotic gradient extending from the cortico-medullary boundary to the inner medullary tip. This gradient is generated in the outer medulla by the countercurrent multiplication of a comparatively small transepithelial difference in osmotic pressure. This small difference, called a single effect, arises from active NaCl reabsorption from thick ascending limbs, which dilutes ascending limb flow relative to flow in vessels and other tubules. In the inner medulla, the gradient may also be generated by the countercurrent multiplication of a single effect, but the single effect has not been definitively identified. Continued experimental investigation and incorporation of the resulting information into mathematic simulations may help to more fully elucidate the inner medullary urine concentrating mechanism.

Keywords

Transient Receptor Potential Channel Outer Medulla Nephron Segment Passive Mechanism Tubular Fluid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

This chapter is an expanded version of two articles published originally as Sands JM, Layton HE. The physiology of urinary concentration: an update. Semin Nephrol. 2009;29(3):178–95, copyright Elsevier Inc.; and Mount DB. The brain in hyponatremia: both culprit and victim. Semin Nephrol. 2009;29(3):196–215, copyright Elsevier Inc., 2009.

This work was supported by National Institutes of Health grants R01-DK41707 to J.M.S., R01-DK42091 to H.E.L., and PO1-DK070756 to D.B.M.

References

  1. 1.
    Sands JM, Layton HE. The physiology of urinary concentration: an update. Semin Nephrol. 2009;29(3): 178–95.PubMedGoogle Scholar
  2. 2.
    Sands JM, Layton HE. The urine concentrating mechanism and urea transporters. In: Alpern RJ, Hebert SC, editors. The Kidney: Physiology and Pathophysiology. 4th ed. San Diego: Academic Press; 2008. p. 1143–78.Google Scholar
  3. 3.
    Robertson GL, Aycinena P, Zerbe RL. Neurogenic disorders of osmoregulation. Am J Med. 1982;72(2):339–53.PubMedGoogle Scholar
  4. 4.
    Uretsky BF, Verbalis JG, Generalovich T, Valdes A, Reddy PS. Plasma vasopressin response to osmotic and hemodynamic stimuli in heart failure. Am J Physiol. 1985;248(3 Pt 2):H396–402.PubMedGoogle Scholar
  5. 5.
    Verbalis JG, Berl T. Disorders of water balance. In: Brenner BM, editor. The Kidney. 8th ed. Philadelphia, PA: Saunders; 2008. p. 459–549.Google Scholar
  6. 6.
    Mount DB. The brain in hyponatremia: both culprit and victim. Semin Nephrol. 2009;29(3):196–215.PubMedGoogle Scholar
  7. 7.
    Davison JM, Gilmore EA, Durr J, Robertson GL, Lindheimer MD. Altered osmotic thresholds for vasopressin secretion and thirst in human pregnancy. Am J Physiol. 1984;246(1 Pt 2):F105–9.PubMedGoogle Scholar
  8. 8.
    Sladek CD, Somponpun SJ. Estrogen receptors: their roles in regulation of vasopressin release for maintenance of fluid and electrolyte homeostasis. Front Neuroendocrinol. 2008;29(1):114–27.PubMedGoogle Scholar
  9. 9.
    Pak TR, Chung WC, Hinds LR, Handa RJ. Estrogen receptor-beta mediates dihydrotestosterone-induced stimulation of the arginine vasopressin promoter in neuronal cells. Endocrinology. 2007;148(7): 3371–82.PubMedGoogle Scholar
  10. 10.
    Somponpun SJ, Sladek CD. Depletion of oestrogen receptor-beta expression in magnocellular arginine vasopressin neurones by hypovolaemia and dehydration. J Neuroendocrinol. 2004;16(6):544–9.PubMedGoogle Scholar
  11. 11.
    McKenna K, Thompson C. Osmoregulation in clinical disorders of thirst appreciation. Clin Endocrinol (Oxf). 1998;49(2):139–52.Google Scholar
  12. 12.
    Bourque CW. Central mechanisms of osmosensation and systemic osmoregulation. Nat Rev Neurosci. 2008;9(7):519–31.PubMedGoogle Scholar
  13. 13.
    Fitzsimons JT. Angiotensin, thirst, and sodium appetite. Physiol Rev. 1998;78(3):583–686.PubMedGoogle Scholar
  14. 14.
    Sakai K, Agassandian K, Morimoto S, Sinnayah P, Cassell MD, Davisson RL, et al. Local production of angiotensin II in the subfornical organ causes elevated drinking. J Clin Invest. 2007;117(4):1088–95.PubMedGoogle Scholar
  15. 15.
    Lazartigues E, Sinnayah P, Augoyard G, Gharib C, Johnson AK, Davisson RL. Enhanced water and salt intake in transgenic mice with brain-restricted overexpression of angiotensin (AT1) receptors. Am J Physiol Regul Integr Comp Physiol. 2008;295(5): R1539–45.PubMedGoogle Scholar
  16. 16.
    McKinley MJ, Walker LL, Alexiou T, Allen AM, Campbell DJ, Di NR, et al. Osmoregulatory fluid intake but not hypovolemic thirst is intact in mice lacking angiotensin. Am J Physiol Regul Integr Comp Physiol. 2008;294(5):R1533–43.PubMedGoogle Scholar
  17. 17.
    Phillips PA, Rolls BJ, Ledingham JG, Morton JJ, Forsling ML. Angiotensin II-induced thirst and vasopressin release in man. Clin Sci (Lond). 1985; 68(6):669–74.Google Scholar
  18. 18.
    Cadnapaphornchai MA, Rogachev B, Summer SN, Chen YC, Gera L, Stewart JM, et al. Evidence for bradykinin as a stimulator of thirst. Am J Physiol Renal Physiol. 2004;286(5):F875–80.PubMedGoogle Scholar
  19. 19.
    Smith D, Moore K, Tormey W, Baylis PH, Thompson CJ. Downward resetting of the osmotic threshold for thirst in patients with SIADH. Am J Physiol Endocrinol Metab. 2004;287(5):E1019–23.PubMedGoogle Scholar
  20. 20.
    Verney EB. The antidiuretic hormone and the factors which determine its release. Proc R Soc Lond B Biol Sci. 1947;135(878):25–106.PubMedGoogle Scholar
  21. 21.
    McKinley MJ, Denton DA, Oldfield BJ, De Oliveira LB, Mathai ML. Water intake and the neural correlates of the consciousness of thirst. Semin Nephrol. 2006;26(3):249–57.PubMedGoogle Scholar
  22. 22.
    Bourque CW, Ciura S, Trudel E, Stachniak TJ, Sharif-Naeini R. Neurophysiological characterization of mammalian osmosensitive neurones. Exp Physiol. 2007;92(3):499–505.PubMedGoogle Scholar
  23. 23.
    Sewards TV, Sewards MA. The awareness of thirst: proposed neural correlates. Conscious Cogn. 2000;9(4):463–87.PubMedGoogle Scholar
  24. 24.
    Oliet SH, Bourque CW. Mechanosensitive channels transduce osmosensitivity in supraoptic neurons. Nature. 1993;364(6435):341–3.PubMedGoogle Scholar
  25. 25.
    McKinley MJ, Cairns MJ, Denton DA, Egan G, Mathai ML, Uschakov A, et al. Physiological and pathophysiological influences on thirst. Physiol Behav. 2004;81(5):795–803.PubMedGoogle Scholar
  26. 26.
    McKinley MJ, Mathai ML, McAllen RM, McClear RC, Miselis RR, Pennington GL, et al. Vasopressin secretion: osmotic and hormonal regulation by the lamina terminalis. J Neuroendocrinol. 2004;16(4): 340–7.PubMedGoogle Scholar
  27. 27.
    McKinley MJ, Mathai ML, Pennington G, Rundgren M, Vivas L. Effect of individual or combined ablation of the nuclear groups of the lamina terminalis on water drinking in sheep. Am J Physiol Regul Integr Comp Physiol. 1999;276(3):R673–83.Google Scholar
  28. 28.
    Egan G, Silk T, Zamarripa F, Williams J, Federico P, Cunnington R, et al. Neural correlates of the emergence of consciousness of thirst. Proc Natl Acad Sci U S A. 2003;100(25):15241–6.PubMedGoogle Scholar
  29. 29.
    Baylis PH, Thompson CJ. Osmoregulation of vasopressin secretion and thirst in health and disease. Clin Endocrinol (Oxf). 1988;29(5):549–76.Google Scholar
  30. 30.
    Shi P, Martinez MA, Calderon AS, Chen Q, Cunningham JT, Toney GM. Intra-carotid hyperosmotic stimulation increases Fos staining in forebrain organum vasculosum laminae terminalis neurones that project to the hypothalamic paraventricular nucleus. J Physiol. 2008;586(Pt 21):5231–45.PubMedGoogle Scholar
  31. 31.
    Zhang Z, Bourque CW. Osmometry in osmosensory neurons. Nat Neurosci. 2003;6:1021–2.PubMedGoogle Scholar
  32. 32.
    Zhang Z, Bourque CW. Calcium permeability and flux through osmosensory transduction channels of isolated rat supraoptic nucleus neurons. Eur J Neurosci. 2006;23(6):1491–500.PubMedGoogle Scholar
  33. 33.
    Colbert HA, Smith TL, Bargmann CI. OSM-9, a novel protein with structural similarity to channels, is required for olfaction, mechanosensation, and olfactory adaptation in Caenorhabditis elegans. J Neurosci. 1997;17(21):8259–69.PubMedGoogle Scholar
  34. 34.
    Liedtke W, Choe Y, Marti-Renom MA, Bell AM, Denis CS, Sali A, et al. Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Cell. 2000;103(3): 525–35.PubMedGoogle Scholar
  35. 35.
    Mizuno A, Matsumoto N, Imai M, Suzuki M. Impaired osmotic sensation in mice lacking TRPV4. Am J Physiol Cell Physiol. 2003;285(1):C96–C101.PubMedGoogle Scholar
  36. 36.
    Strotmann R, Harteneck C, Nunnenmacher K, Schultz G, Plant TD. OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity. Nat Cell Biol. 2000;2(10):695–702.PubMedGoogle Scholar
  37. 37.
    Oliet SH, Bourque CW. Gadolinium uncouples mechanical detection and osmoreceptor potential in supraoptic neurons. Neuron. 1996;16(1):175–81.PubMedGoogle Scholar
  38. 38.
    Qiu DL, Shirasaka T, Chu CP, Watanabe S, Yu NS, Katoh T, et al. Effect of hypertonic saline on rat hypothalamic paraventricular nucleus magnocellular neurons in vitro. Neurosci Lett. 2004;355(1–2): 117–20.PubMedGoogle Scholar
  39. 39.
    Liedtke W, Friedman JM. Abnormal osmotic regulation in trpv4−/− mice. Proc Natl Acad Sci U S A. 2003;100(23):13698–703.PubMedGoogle Scholar
  40. 40.
    Tsushima H, Mori M. Antidipsogenic effects of a TRPV4 agonist, 4alpha-phorbol 12,13-didecanoate, injected into the cerebroventricle. Am J Physiol Regul Integr Comp Physiol. 2006;290(6):R1736–41.PubMedGoogle Scholar
  41. 41.
    Ciura S, Bourque CW. Transient receptor potential vanilloid 1 is required for intrinsic osmoreception in organum vasculosum lamina terminalis neurons and for normal thirst responses to systemic hyperosmolality. J Neurosci. 2006;26(35):9069–75.PubMedGoogle Scholar
  42. 42.
    Sharif NR, Witty MF, Seguela P, Bourque CW. An N-terminal variant of Trpv1 channel is required for osmosensory transduction. Nat Neurosci. 2006;9(1): 93–8.Google Scholar
  43. 43.
    Suzuki M, Sato J, Kutsuwada K, Ooki G, Imai M. Cloning of a stretch-inhibitable nonselective cation channel. J Biol Chem. 1999;274(10):6330–5.PubMedGoogle Scholar
  44. 44.
    Taylor AC, McCarthy JJ, Stocker SD. Mice lacking the transient receptor vanilloid potential 1 channel display normal thirst responses and central Fos activation to hypernatremia. Am J Physiol Regul Integr Comp Physiol. 2008;294(4):R1285–93.PubMedGoogle Scholar
  45. 45.
    Wainwright A, Rutter AR, Seabrook GR, Reilly K, Oliver KR. Discrete expression of TRPV2 within the hypothalamo-neurohypophysial system: Implications for regulatory activity within the hypothalamic-pituitary-adrenal axis. J Comp Neurol. 2004;474(1): 24–42.PubMedGoogle Scholar
  46. 46.
    Bourque CW, Voisin DL, Chakfe Y. Stretch-inactivated cation channels: cellular targets for modulation of osmosensitivity in supraoptic neurons. Prog Brain Res. 2002;139:85–94.PubMedGoogle Scholar
  47. 47.
    Voisin DL, Chakfe Y, Bourque CW. Coincident detection of CSF Na+ and osmotic pressure in osmoregulatory neurons of the supraoptic nucleus. Neuron. 1999;24(2):453–60.PubMedGoogle Scholar
  48. 48.
    McKinley MJ, Denton DA, Weisinger RS. Sensors for antidiuresis and thirst—osmoreceptors or CSF sodium detectors? Brain Res. 1978;141(1):89–103.PubMedGoogle Scholar
  49. 49.
    Chakfe Y, Bourque CW. Excitatory peptides and osmotic pressure modulate mechanosensitive cation channels in concert. Nat Neurosci. 2000;3(6):572–9.PubMedGoogle Scholar
  50. 50.
    Zhang Z, Bourque CW. Amplification of transducer gain by angiotensin II-mediated enhancement of cortical actin density in osmosensory neurons. J Neurosci. 2008;28(38):9536–44.PubMedGoogle Scholar
  51. 51.
    Mikkelsen JD, Hay-Schmidt A, Kiss A. Serotonergic stimulation of the rat hypothalamo-pituitary-adrenal axis: interaction between 5-HT1A and 5-HT2A receptors. Ann N Y Acad Sci. 2004;1018:65–70.PubMedGoogle Scholar
  52. 52.
    Ho SS, Chow BK, Yung WH. Serotonin increases the excitability of the hypothalamic paraventricular nucleus magnocellular neurons. Eur J Neurosci. 2007;25(10):2991–3000.PubMedGoogle Scholar
  53. 53.
    Stephenson CP, Hunt GE, Topple AN, McGregor IS. The distribution of 3,4-methylenedioxymethamphetamine “Ecstasy”-induced c-fos expression in rat brain. Neuroscience. 1999;92(3):1011–23.PubMedGoogle Scholar
  54. 54.
    Fallon JK, Shah D, Kicman AT, Hutt AJ, Henry JA, Cowan DA, et al. Action of MDMA (ecstasy) and its metabolites on arginine vasopressin release. Ann N Y Acad Sci. 2002;965:399–409.PubMedGoogle Scholar
  55. 55.
    Campbell GA, Rosner MH. The agony of ecstasy: MDMA (3,4-methylenedioxymethamphetamine) and the kidney. Clin J Am Soc Nephrol. 2008;3(6): 1852–60.PubMedGoogle Scholar
  56. 56.
    Knepper MA, Stephenson JL. Urinary concentrating and diluting processes. In: Andreoli TE, Hoffman JF, Fanestil DD, Schultz SG, editors. Physiology of membrane disorders. 2nd ed. New York: Plenum; 1986. p. 713–26.Google Scholar
  57. 57.
    Hai MA, Thomas S. The time-course of changes in renal tissue composition during lysine vasopressin infusion in the rat. Pfleugers Arch. 1969;310:297–319.Google Scholar
  58. 58.
    Knepper MA. Measurement of osmolality in kidney slices using vapor pressure osmometry. Kidney Int. 1982;21:653–5.PubMedGoogle Scholar
  59. 59.
    Pannabecker TL, Dantzler WH, Layton HE, Layton AT. Role of three-dimensional architecture in the urine concentrating mechanism of the rat renal inner medulla. Am J Physiol Renal Physiol. 2008;295(5):F1271–85.PubMedGoogle Scholar
  60. 60.
    Kriz W. Der architektonische und funktionelle Aufbau der Rattenniere. Z Zellforsch. 1967;82: 495–535.PubMedGoogle Scholar
  61. 61.
    Kokko JP, Rector FC. Countercurrent multiplication system without active transport in inner medulla. Kidney Int. 1972;2:214–23.PubMedGoogle Scholar
  62. 62.
    Stephenson JL. Concentration of urine in a central core model of the renal counterflow system. Kidney Int. 1972;2:85–94.PubMedGoogle Scholar
  63. 63.
    Zimmerhackl BL, Robertson CR, Jamison RL. The medullary microcirculation. Kidney Int. 1987;31(2): 641–7.PubMedGoogle Scholar
  64. 64.
    Pallone TL, Turner MR, Edwards A, Jamison RL. Countercurrent exchange in the renal medulla. Am J Physiol Regul Integr Comp Physiol. 2003;284(5): R1153–75.PubMedGoogle Scholar
  65. 65.
    Kuhn W, Ryffel K. Herstellung konzentrierrter Lösungen aus verdünnten durch blosse Membranwirkung: Ein Modellversuch zur Funktion der Niere. Hoppe Seylers Z Physiol Chem. 1942;276:145–78.Google Scholar
  66. 66.
    Gottschalk CW, Mylle M. Micropuncture study of the mammalian urinary concentrating mechanism: evidence for the countercurrent hypothesis. Am J Physiol. 1959;196:927–36.PubMedGoogle Scholar
  67. 67.
    Rocha AS, Kokko JP. Sodium chloride and water transport in the medullary thick ascending limb of Henle. Evidence for active chloride transport. J Clin Invest. 1973;52:612–23.PubMedGoogle Scholar
  68. 68.
    Ullrich KJ, Schmidt-Nielsen B, O’Dell R, Pehling G, Gottschalk CW, Lassiter WE, et al. Micropuncture study of composition of proximal and distal tubular fluid in rat kidney. Am J Physiol. 1963;204:527–31.PubMedGoogle Scholar
  69. 69.
    Jamison RL, Kriz W. Urinary concentrating mechanism. Structure and function. New York: Oxford University Press; 1982.Google Scholar
  70. 70.
    Chou C-L, Knepper MA, Layton HE. Urinary concentrating mechanism: the role of the inner medulla. Semin Nephrol. 1993;13(2):168–81.PubMedGoogle Scholar
  71. 71.
    Fenton RA, Chou C-L, Stewart GS, Smith CP, Knepper MA. 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. 2004;101(19):7469–74.PubMedGoogle Scholar
  72. 72.
    Layton HE, Knepper MA, Chou C-L. Permeability criteria for effective function of passive countercurrent multiplier. Am J Physiol. 1996;270(1):F9–F20.PubMedGoogle Scholar
  73. 73.
    Moore LC, Marsh DJ. How descending limb of Henle’s loop permeability affects hypertonic urine formation. Am J Physiol. 1980;239:F57–71.PubMedGoogle Scholar
  74. 74.
    Wexler AS, Kalaba RE, Marsh DJ. Passive, one-dimensional countercurrent models do not simulate hypertonic urine formation. Am J Physiol. 1987;253:F1020–30.PubMedGoogle Scholar
  75. 75.
    Wexler AS, Kalaba RE, Marsh DJ. Three-dimensional anatomy and renal concentrating mechanism. I. Modelling results. Am J Physiol. 1991;260: F368–83.PubMedGoogle Scholar
  76. 76.
    Knepper MA, Chou C-L, Layton HE. How is urine concentrated by the renal inner medulla? Contrib Nephrol. 1993;102:144–60.PubMedGoogle Scholar
  77. 77.
    Jen JF, Stephenson JL. Externally driven countercurrent multiplication in a mathematical model of the urinary concentrating mechanism of the renal inner medulla. Bull Math Biol. 1994;56(3):491–514.PubMedGoogle Scholar
  78. 78.
    Chou C-L, Knepper MA. In vitro perfusion of chinchilla thin limb segments: urea and NaCl permeabilities. Am J Physiol Renal Physiol. 1993;264: F337–43.Google Scholar
  79. 79.
    Thomas SR. Inner medullary lactate production and accumulation: a vasa recta model. Am J Physiol Renal Physiol. 2000;279:F468–81.PubMedGoogle Scholar
  80. 80.
    Hervy S, Thomas SR. Inner medullary lactate production and urine-concentrating mechanism: a flat medullary model. Am J Physiol Renal Physiol. 2003;284(1):F65–81.PubMedGoogle Scholar
  81. 81.
    Knepper MA, Saidel GM, Hascall VC, Dwyer T. Concentration of solutes in the renal inner medulla: interstitial hyaluronan as a mechano-osmotic transducer. Am J Physiol Renal Physiol. 2003;284(3): F433–46.PubMedGoogle Scholar
  82. 82.
    Layton AT, Pannabecker TL, Dantzler WH, Layton HE. Two modes for concentrating urine in rat inner medulla. Am J Physiol Renal Physiol. 2004;287(4): F816–39.PubMedGoogle Scholar
  83. 83.
    Hargitay B, Kuhn W. Das Multiplikationsprinzip als Grundlage der Harnkonzentrierung in der Niere. Z Elektrochem. 1951;55:539–58.Google Scholar
  84. 84.
    Vehaskari VM, Hering-Smith KS, Moskowitz DW, Weiner ID, Hamm LL. Effect of epidermal growth factor on sodium transport in the cortical collecting tubule. Am J Physiol. 1989;256:F803–9.PubMedGoogle Scholar
  85. 85.
    Layton AT, Layton HE. A region-based mathematical model of the urine concentrating mechanism in the rat outer medulla. I. Formulation and base-case results. Am J Physiol Renal Physiol. 2005;289(6): F1346–66.PubMedGoogle Scholar
  86. 86.
    Layton AT, Layton HE. A region-based mathematical model of the urine concentrating mechanism in the rat outer medulla. II. Parameter sensitivity and tubular inhomogeneity. Am J Physiol Renal Physiol. 2005;289(6):F1367–81.PubMedGoogle Scholar
  87. 87.
    de Rouffignac C. The urinary concentrating mechanism. In: Kinne RKH, editor. Urinary concentrating mechanisms. Comparative physiology. Basel: Karger; 1990. p. 31–102.Google Scholar
  88. 88.
    Macri P, Breton S, Marsolais M, Lapointe JY, Laprade R. Hypertonicity decreases basolateral K+ and Cl− conductances in rabbit proximal convoluted tubule. J Membr Biol. 1997;155(3):229–37.PubMedGoogle Scholar
  89. 89.
    Morgan T, Berliner RW. Permeability of the loop of Henle, vasa recta, and collecting duct to water, urea, and sodium. Am J Physiol. 1968;215:108–15.PubMedGoogle Scholar
  90. 90.
    Imai M, Kokko JP. Sodium, chloride, urea, and water transport in the thin ascending limb of Henle. J Clin Invest. 1974;53:393–402.PubMedGoogle Scholar
  91. 91.
    Kokko JP. Sodium chloride and water transport in the descending limb of Henle. J Clin Invest. 1970;49:1838–46.PubMedGoogle Scholar
  92. 92.
    Kokko JP. Urea transport in the proximal tubule and the descending limb of Henle. J Clin Invest. 1972;51:1999–2008.PubMedGoogle Scholar
  93. 93.
    Gamble JL, McKhann CF, Butler AM, Tuthill E. An economy of water in renal function referable to urea. Am J Physiol. 1934;109:139–54.Google Scholar
  94. 94.
    Niesel W, Röskenbleck H. Konzentrierung von Lösungen unterschiedlicher Zusammensetzung durch alleinige Gegenstromdiffusion und Geggenstromosmose als möglicher Mechanismus der Harnkonzentrierung. Pflfiegers Arch. 1965;283: 230–41.Google Scholar
  95. 95.
    Layton HE, Davies JM. Distributed solute and water reabsorption in a central core model of the renal medulla. Math Biosci. 1993;116:169–96.PubMedGoogle Scholar
  96. 96.
    Wang X, Wexler AS, Marsh DJ. The effect of solution non-ideality on membrane transport in three-dimensional models of the renal concentrating mechanism. Bull Math Biol. 1994;56(3):515–46.PubMedGoogle Scholar
  97. 97.
    Thomas SR. Cycles and separations in a model of the renal medulla. Am J Physiol Renal Physiol. 1998;275(5):F671–90.Google Scholar
  98. 98.
    Stephenson JL, Zhang Y, Eftekhari A, Tewarson RP. Electrolyte transport in a central core model of the renal medulla. Am J Physiol. 1989;253:F982–97.Google Scholar
  99. 99.
    Stephenson JL, Zhang Y, Tewarson RP. Electrolyte, urea, and water transport in a two-nephron central core model of the renal medulla. Am J Physiol. 1989;257:F388–413.Google Scholar
  100. 100.
    Thomas SR, Wexler AS. Inner medullary external osmotic driving force in a 3D model of the renal concentrating mechanism. Am J Physiol. 1995;269: F159–71.PubMedGoogle Scholar
  101. 101.
    Pannabecker TL, Dantzler WH. Three-dimensional lateral and vertical relationships of inner medullary loops of Henle and collecting ducts. Am J Physiol Renal Physiol. 2004;287(4):F767–74.PubMedGoogle Scholar
  102. 102.
    Pannabecker TL, Abbott DE, Dantzler WH. Three-dimensional functional reconstruction of inner medullary thin limbs of Henle’s loop. Am J Physiol Renal Physiol. 2004;286(1):F38–45.PubMedGoogle Scholar
  103. 103.
    Schmidt-Nielsen B. The renal concentrating mechanism in insects and mammals: a new hypothesis involving hydrostatic pressures. Am J Physiol. 1995;268:R1087–100.PubMedGoogle Scholar
  104. 104.
    Tomita K, Pisano JJ, Knepper MA. Control of sodium and potassium transport in the cortical collecting duct of the rat. Effects of bradykinin, vasopressin, and deoxycorticosterone. J Clin Invest. 1985;76:132–6.PubMedGoogle Scholar
  105. 105.
    Sands JM, Knepper MA. Urea permeability of mammalian inner medullary collecting duct system and papillary surface epithelium. J Clin Invest. 1987;79: 138–47.PubMedGoogle Scholar
  106. 106.
    Sands JM, Nonoguchi H, Knepper MA. Vasopressin effects on urea and H2O transport in inner medullary collecting duct subsegments. Am J Physiol. 1987;253:F823–32.PubMedGoogle Scholar
  107. 107.
    Hoffert JD, Fenton RA, Moeller HB, Simons B, Tchapyjnikov D, McDill BW, et al. Vasopressin-stimulated Increase in Phosphorylation at Ser269 Potentiates Plasma Membrane Retention of Aquaporin-2. J Biol Chem. 2008;283(36): 24617–27.PubMedGoogle Scholar
  108. 108.
    Hoffert JD, Pisitkun T, Wang GH, Shen RF, Knepper MA. Dynamics of aquaporin-2 serine-261 phosphorylation in response to short-term vasopressin treatment in collecting duct. Am J Physiol Renal Physiol. 2007;292(2):F691–700.PubMedGoogle Scholar
  109. 109.
    Hoffert JD, Pisitkun T, Wang G, Shen R-F, Knepper MA. Quantitative phosphoproteomics of vasopressin-sensitive renal cells: regulation of aquaporin-2 phosphorylation at two sites. Proc Natl Acad Sci U S A. 2006;103(18):7159–64.PubMedGoogle Scholar
  110. 110.
    Fenton RA, Moeller HB, Hoffert JD, Yu MJ, Nielsen S, Knepper MA. Acute regulation of aquaporin-2 phosphorylation at Ser-264 by vasopressin. PNAS. 2008;105(8):3134–9.PubMedGoogle Scholar
  111. 111.
    Nielsen S, Frokiaer J, Marples D, Kwon ED, Agre P, Knepper M. Aquaporins in the kidney: from molecules to medicine. Physiol Rev. 2002;82:205–44.PubMedGoogle Scholar
  112. 112.
    Wade JB, Stetson DL, Lewis SA. ADH action: evidence for a membrane shuttle mechanism. Ann N Y Acad Sci. 1981;372:106–17.PubMedGoogle Scholar
  113. 113.
    Jamison RL, Buerkert J, Lacy FB. A micropuncture study of collecting tubule function in rats with hereditary diabetes insipidus. J Clin Invest. 1971;50: 2444–52.PubMedGoogle Scholar
  114. 114.
    Fenton RA, Knepper MA. Urea and renal function in the 21st century: insights from knockout mice. J Am Soc Nephrol. 2007;18(3):679–88.PubMedGoogle Scholar
  115. 115.
    Fröhlich O, Klein JD, Smith PM, Sands JM, Gunn RB. Urea transport in MDCK cells that are stably transfected with UT-A1. Am J Physiol Cell Physiol. 2004;286(6):C1264–70.PubMedGoogle Scholar
  116. 116.
    Klein JD, Blount MA, Fröhlich O, Denson C, Tan X, Sim J, et al. 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. 2010;298(4):F935–40.PubMedGoogle Scholar
  117. 117.
    Shayakul C, Steel A, Hediger MA. Molecular cloning and characterization of the vasopressin-regulated urea transporter of rat kidney collecting ducts. J Clin Invest. 1996;98(11):2580–7.PubMedGoogle Scholar
  118. 118.
    Promeneur D, Rousselet G, Bankir L, Bailly P, Cartron JP, Ripoche P, et al. Evidence for distinct vascular and tubular urea transporters in the rat kidney. J Am Soc Nephrol. 1996;7(6):852–60.PubMedGoogle Scholar
  119. 119.
    Fenton RA, Stewart GS, Carpenter B, Howorth A, Potter EA, Cooper GJ, et al. Characterization of the mouse urea transporters UT-A1 and UT-A2. Am J Physiol Renal Physiol. 2002;283(4):F817–25.PubMedGoogle Scholar
  120. 120.
    Chen G, Fröhlich O, Yang Y, Klein JD, Sands JM. Loss of N-linked glycosylation reduces urea transporter UT-A1 response to vasopressin. J Biol Chem. 2006;281(37):27436–42.PubMedGoogle Scholar
  121. 121.
    Mistry AC, Mallick R, Fröhlich O, Klein JD, Rehm A, Chen G, et al. The UT-A1 urea transporter interacts with snapin, a snare-associated protein. J Biol Chem. 2007;282(41):30097–106.PubMedGoogle Scholar
  122. 122.
    Terris JM, Knepper MA, Wade JB. UT-A3: localization and characterization of an additional urea transporter isoform in the IMCD. Am J Physiol Renal Physiol. 2001;280(2):F325–32.PubMedGoogle Scholar
  123. 123.
    Stewart GS, Fenton RA, Wang W, Kwon TH, White SJ, Collins VM, et al. The basolateral expression of mUT-A3 in the mouse kidney. Am J Physiol Renal Physiol. 2004;286(5):F979–87.PubMedGoogle Scholar
  124. 124.
    Blount MA, Klein JD, Martin CF, Tchapyjnikov D, Sands JM. Forskolin stimulates phosphorylation and membrane accumulation of UT-A3. Am J Physiol Renal Physiol. 2007;293(4):F1308–13.PubMedGoogle Scholar
  125. 125.
    You G, Smith CP, Kanai Y, Lee W-S, Stelzner M, Hediger MA. Cloning and characterization of the vasopressin-regulated urea transporter. Nature. 1993;365:844–7.PubMedGoogle Scholar
  126. 126.
    Olives B, Neau P, Bailly P, Hediger MA, Rousselet G, Cartron JP, et al. Cloning and functional expression of a urea transporter from human bone marrow cells. J Biol Chem. 1994;269(50):31649–52.PubMedGoogle Scholar
  127. 127.
    Yang BX, Verkman AS. Urea transporter UT3 functions as an efficient water channel—Direct evidence for a common water/urea pathway. J Biol Chem. 1998;273(16):9369–72.PubMedGoogle Scholar
  128. 128.
    Yang B, Bankir L, Gillespie A, Epstein CJ, Verkman AS. Urea-selective concentrating defect in transgenic mice lacking urea transporter UT-B. J Biol Chem. 2002;277:10633–7.PubMedGoogle Scholar
  129. 129.
    Sidoux-Walter F, Lucien N, Olivès B, Gobin R, Rousselet G, Kamsteeg EJ, et al. At physiological expression levels the Kidd blood group/urea transporter protein is not a water channel. J Biol Chem. 1999;274(42):30228–35.PubMedGoogle Scholar
  130. 130.
    Yang B, Verkman AS. Analysis of double knockout mice lacking aquaporin-1 and urea transporter UT-B. J Biol Chem. 2002;277(39):36782–6.PubMedGoogle Scholar
  131. 131.
    Zhang C, Sands JM, Klein JD. Vasopressin rapidly increases the phosphorylation of the UT-A1 urea transporter activity in rat IMCDs through PKA. Am J Physiol Renal Physiol. 2002;282(1):F85–90.PubMedGoogle Scholar
  132. 132.
    Blount MA, Mistry AC, Fröhlich O, Price SR, Chen G, Sands JM, et al. 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. 2008;295(1):F295–9.PubMedGoogle Scholar
  133. 133.
    Hwang S, Gunaratne R, Rinschen MM, Yu M-J, Pisitkun T, Hoffert JD, et al. Vasporessin increases phosphorylation of ser84 and ser486 in Slc14a2 collecting duct urea transporters. Am J Physiol Renal Physiol. 2010;299(3):F559–67.PubMedGoogle Scholar
  134. 134.
    Mistry AC, Mallick R, Klein JD, Sands JM, Froehlich O. Functional characterization of the central hydrophilic linker region of the urea transporter UT-A1: cAMP activation and snapin binding. Am J Physiol Cell Physiol. 2010;298:C1431–7.PubMedGoogle Scholar
  135. 135.
    Smith CP, Potter EA, Fenton RA, Stewart GS. Characterization of a human colonic cDNA encoding a structurally novel urea transporter, UT-A6. Am J Physiol Cell Physiol. 2004;287(4):C1087–93.PubMedGoogle Scholar
  136. 136.
    Stewart GS, O’Brien JH, Smith CP. Ubiquitination regulates the plasma membrane expression of renal UT-A urea transporters. Am J Physiol Cell Physiol. 2008;295:C121–9.PubMedGoogle Scholar
  137. 137.
    Chen G, Huang H, Fröhlich O, Yang Y, Klein JD, Price SR, et al. MDM2 E3 ubiquitin ligase mediates UT-A1 urea transporter ubiquitination and degradation. Am J Physiol Renal Physiol. 2008;295(5):F1528–34.PubMedGoogle Scholar
  138. 138.
    Gillin AG, Sands JM. Characteristics of osmolarity-stimulated urea transport in rat IMCD. Am J Physiol. 1992;262:F1061–7.PubMedGoogle Scholar
  139. 139.
    Blessing NW, Blount MA, Sands JM, Martin CF, Klein JD. Urea transporters UT-A1 and UT-A3 accumulate in the plasma membrane in response to increased hypertonicity. Am J Physiol Renal Physiol. 2008;295(5):F1336–41.PubMedGoogle Scholar
  140. 140.
    Klein JD, Fröhlich O, Blount MA, Martin CF, Smith TD, Sands JM. Vasopressin increases plasma membrane accumulation of urea transporter UT-A1 in rat inner medullary collecting ducts. J Am Soc Nephrol. 2006;17:2680–6.PubMedGoogle Scholar
  141. 141.
    Harrington AR, Valtin H. Impaired urinary concentration after vasopressin and its gradual correction in hypothalamic diabetes insipidus. J Clin Invest. 1968;47:502–10.PubMedGoogle Scholar
  142. 142.
    Kim D-U, Sands JM, Klein JD. Role of vasopressin in diabetes mellitus-induced changes in medullary transport proteins involved in urine concentration in Brattleboro rats. Am J Physiol Renal Physiol. 2004;286:F760–66.PubMedGoogle Scholar
  143. 143.
    Nakayama Y, Naruse M, Karakashian A, Peng T, Sands JM, Bagnasco SM. Cloning of the rat Slc14a2 gene and genomic organization of the UT-A urea transporter. Biochim Biophys Acta. 2001;1518: 19–26.PubMedGoogle Scholar
  144. 144.
    Nakayama Y, Peng T, Sands JM, Bagnasco SM. The TonE/TonEBP pathway mediates tonicity-responsive regulation of UT-A urea transporter expression. J Biol Chem. 2000;275(49):38275–80.PubMedGoogle Scholar
  145. 145.
    Sands JM, Gargus JJ, Fröhlich O, Gunn RB, Kokko JP. Urinary concentrating ability in patients with Jk(a-b-) blood type who lack carrier-mediated urea transport. J Am Soc Nephrol. 1992;2:1689–96.PubMedGoogle Scholar
  146. 146.
    Bankir L, Chen K, Yang B. Lack of UT-B in vasa recta and red blood cells prevents urea-induced improvement of urinary concentrating ability. Am J Physiol Renal Physiol. 2004;286(1):F144–51.PubMedGoogle Scholar
  147. 147.
    Klein JD, Sands JM, Qian L, Wang X, Yang B. Upregulation of urea transporter UT-A2 and water channels AQP2 and AQP3 in mice lacking urea transporter UT-B. J Am Soc Nephrol. 2004;15(5): 1161–7.PubMedGoogle Scholar
  148. 148.
    Layton AT. Role of UTB urea transporters in the urine concentrating mechanism of the rat kidney. Bull Math Biol. 2007;69(3):887–929.PubMedGoogle Scholar
  149. 149.
    Edwards A, Pallone TL. Facilitated transport in vasa recta: Theoretical effects on solute exchange in the medullary microcirculation. Am J Physiol Renal Physiol. 1997;272(4):F505–14.Google Scholar
  150. 150.
    Edwards A, Pallone TL. A multiunit model of solute and water removal by inner medullary vasa recta. Am J Physiol Heart Circ Physiol. 1998;274(4): H1202–10.Google Scholar
  151. 151.
    Berliner RW, Levinsky NG, Davidson DG, Eden M. Dilution and concentration of the urine and the action of antidiuretic hormone. Am J Med. 1958;24:730–44.PubMedGoogle Scholar
  152. 152.
    Sands JM. Critical role of urea in the urine-concentrating mechanism. J Am Soc Nephrol. 2007;18(3): 670–1.PubMedGoogle Scholar
  153. 153.
    Lemley KV, Kriz W. Cycles and separations: the histotopography of the urinary concentrating process. Kidney Int. 1987;31:538–48.PubMedGoogle Scholar
  154. 154.
    Pannabecker TL, Dantzler WH. Three-dimensional architecture of inner medullary vasa recta. Am J Physiol Renal Physiol. 2006;290(6):F1355–66.PubMedGoogle Scholar
  155. 155.
    Knepper MA, Roch-Ramel F. Pathways of urea transport in the mammalian kidney. Kidney Int. 1987;31:629–33.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Jeff M. Sands
    • 1
    Email author
  • David B. Mount
    • 2
  • Harold E. Layton
    • 3
  1. 1.Department of Medicine, Renal DivisionEmory UniversityAtlantaUSA
  2. 2.Renal DivisionVA Boston Healthcare System, Brigham and Women’s Hospital, Harvard Medical SchoolBostonUSA
  3. 3.Department of MathematicsDuke UniversityDurhamUSA

Personalised recommendations