Na+,K+-ATPase Activity and Subunit Protein Expression: Ontogeny and Effects of Exogenous and Endogenous Steroids on the Cerebral Cortex and Renal Cortex of Sheep


We examined the effects of development, exogenous, and endogenous glucocorticoids on Na+,K+-ATPase activity and subunit protein expression in ovine cerebral cortices and renal cortices. Ewes at 60%, 80%, and 90% gestation, newborns, and adults received 4 dexamethasone or placebo injections. Cerebral cortex Na+,K+-ATPase activity was higher (P <.05) in placebo-treated newborns than fetuses of placebo-treated ewes and adults, α1-expression was higher at 90% gestation than the other ages; α2-expression was higher in newborns than fetuses; α3-expression was higher in newborns than 60% gestation; β1-expression was higher in newborns than the other ages, and β2-expression higher at 60% than 80% and 90% gestation, and in adults. Renal cortex Na+,K+-ATPase activity was higher in placebo-treated adults and newborns than fetuses. Cerebral cortex Na+,K+-ATPase activity was higher in dexamethasone- than placebo-treated adults, and α1-expression higher in fetuses of dexamethasone- than placebo-treated ewes at 60% and 80% gestation. Renal cortex Na+,K+-ATPase activity and α1-expression were higher in fetuses of dexamethasone-than placebo-treated ewes at each gestational age, and β1-expression was higher in fetuses of dexamethasone-than placebo-treated ewes at 90% gestation and in dexamethasone-than placebo-treated adults. Cerebral cortex Na+,K+-ATPase activity, α1-expression, β1-expression, and renal cortex α1-expression correlated directly with increases in fetal cortisol. In conclusion, Na+,K+-ATPase activity and subunit expression exhibit specific developmental patterns in brain and kidney; exogenous glucocorticoids regulate activity and subunit expression in brain and kidney at some ages; endogenous increases in fetal cortisol regulate cerebral Na+,K+-ATPase, but exogenous glucocorticoids have a greater effect on renal than cerebral Na+,K+-ATPase.

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  1. 1.

    Skou JC. The Na,K-pump. Methods Enzymol. 1988;156:1–25.

  2. 2.

    Mobasheri A, Avila J, Cozar-Castellano I, et al. Na+, K+-ATPase isozyme diversity; comparative biochemistry and physiological implications of novel functional interactions. Biosci Rep. 2000;20 (2): 51–91.

  3. 3.

    Jahnukainen T, Chen M, Berg U, et al. Antenatal glucocorticoids and renal function after birth. Semin Neonatol. 2001;6 (4): 351–355.

  4. 4.

    Therien AG, Blostein R. Mechanisms of sodium pump regulation. Am J Physiol Cell Physiol. 2000;279 (3): C541–C566.

  5. 5.

    Chow DC, Forte JG. Functional significance of the beta-subunit for heterodimeric P-type ATPases. J Exp Biol. 1995;198 (pt 1): 1–17.

  6. 6.

    Blanco G, Mercer RW. Isozymes of the Na-K-ATPase: heterogeneity in structure, diversity in function. Am J Physiol. 1998;275 (5 pt 2): F633–F650.

  7. 7.

    Lopez LB, Quintas LE, Noel F. Influence of development on Na(+)/K(+)-ATPase expression: isoform- and tissue-dependency. Comp Biochem Physiol A Mol Integr Physiol. 2002;131 (2): 323–333.

  8. 8.

    Horisberger JD, Lemas V, Kraehenbuhl JP, et al. Structure-function relationship of Na,K-ATPase. Annu Rev Physiol. 1991;53 (6): 565–584.

  9. 9.

    Hieber V, Siegel GJ, Fink DJ, et al. Differential distribution of (Na, K)-ATPase alpha isoforms in the central nervous system. Cell Mol Neurobiol. 1991;11 (2): 253–262.

  10. 10.

    Shyjan AW, Levenson R. Antisera specific for the alpha 1, alpha 2, alpha 3, and beta subunits of the Na,K-ATPase: differential expression of alpha and beta subunits in rat tissue membranes. Biochemistry. 1989;28 (11): 4531–4535.

  11. 11.

    Watts AG, Sanchez-Watts G, Emanuel JR, et al. Cell-specific expression of mRNAs encoding Na+,K(+)-ATPase alpha- and beta-subunit isoforms within the rat central nervous system. Proc Natl Acad Sci U S A. 1991;88 (16): 7425–7429.

  12. 12.

    Martin-Vasallo P, Wetzel RK, Garcia-Segura LM, et al. Oligodendrocytes in brain and optic nerve express the beta3 subunit isoform of Na,K-ATPase. Glia. 2000;31 (3): 206–218.

  13. 13.

    Herrera VL, Cova T, Sassoon D, et al. Developmental cell-specific regulation of Na(+)-K(+)-ATPase alpha 1-, alpha 2-, and alpha 3-isoform gene expression. Am J Physiol. 1994;266 (5 pt 1): C1301–C1312.

  14. 14.

    Orlowski J, Lingrel JB. Tissue-specific and developmental regulation of rat Na,K-ATPase catalytic alpha isoform and beta subunit mRNAs. J Biol Chem. 1988;263 (21): 10436–10442.

  15. 15.

    Jaisser F, Jaunin P, Geering K, et al. Modulation of the Na, K-pump function by beta subunit isoforms. J Gen Physiol. 1994;103 (4): 605–623.

  16. 16.

    Berry LM, Polk DH, Ikegami M, et al. Preterm newborn lamb renal and cardiovascular responses after fetal or maternal antenatal betamethasone. Am J Physiol. 1997;272 (6 pt 2): R1972–R1979.

  17. 17.

    Stonestreet BS, Hansen NB, Laptook AR, et al. Glucocorticoid accelerates renal functional maturation in fetal lambs. Early Hum Dev. 1983;8 (3–4): 331–341.

  18. 18.

    Jobe AH. Animal models of antenatal corticosteroids: clinical implications. Clin Obstet Gynecol. 2003;46 (1): 174–189.

  19. 19.

    Effect of corticosteroids for fetal maturation on perinatal outcomes. NIH consensus development panel on the effect of corticosteroids for fetal maturation on perinatal outcomes.Jama. 1995;273 (5): 413–418.

  20. 20.

    Stonestreet BS, Sadowska GB, McKnight AJ, et al. Exogenous and endogenous corticosteroids modulate blood-brain barrier development in the ovine fetus. Am J Physiol Regul Integr Comp Physiol. 2000;279 (2): R468–R477.

  21. 21.

    Sysyn GD, Petersson KH, Patlak CS, et al. Effects of postnatal dexamethasone on blood-brain barrier permeability and brain water content in newborn lambs. Am J Physiol Regul Integr Comp Physiol. 2001;280 (2): R547–R553.

  22. 22.

    Ballard PL, Ballard RA. Scientific basis and therapeutic regimens for use of antenatal glucocorticoids. Am J Obstet Gynecol. 1995;173 (1): 254–262.

  23. 23.

    Yeh TF, Lin YJ, Lin HC, et al. Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity. N Engl J Med. 2004;350 (13): 1304–1313.

  24. 24.

    Stonestreet BS, Elitt CM, Markowitz J, et al. Effects of antenatal corticosteroids on regional brain and non-neural tissue water content in the ovine fetus. J Soc Gynecol Investig. 2003;10 (2): 59–66.

  25. 25.

    Stonestreet BS, Petersson KH, Sadowska GB, et al. Antenatal steroids decrease blood-brain barrier permeability in the ovine fetus. Am J Physiol. 1999;276 (2 pt 2): R283–R289.

  26. 26.

    Kim CR, Sadowska GB, Petersson KH, et al. Effects of postnatal steroids on Na+/K+-ATPase activity and alpha1- and beta1-subunit protein expression in the cerebral cortex and renal cortex of newborn lambs. Reprod Fertil Dev. 2006;18 (4): 413–423.

  27. 27.

    Wintour EM, Alcorn D, McFarlane A, et al. Effect of maternal glucocorticoid treatment on fetal fluids in sheep at 0.4 gestation. Am J Physiol. 1994;266 (4 pt 2): R1174–R1181.

  28. 28.

    Omar SA, DeCristofaro JD, Agarwal BI, et al. Effects of prenatal steroids on water and sodium homeostasis in extremely low birth weight neonates. Pediatrics. 1999;104 (3 pt 1): 482–488.

  29. 29.

    Petershack JA, Nagaraja SC, Guillery EN. Role of glucocorticoids in the maturation of renal cortical Na+-K+-ATPase during fetal life in sheep. Am J Physiol. 1999;276 (6 pt 2): R1825–R1832.

  30. 30.

    al-Dahan J, Stimmler L, Chantler C, et al. The effect of antenatal dexamethasone administration on glomerular filtration rate and renal sodium excretion in premature infants. Pediatr Nephrol. 1987;1 (2): 131–135.

  31. 31.

    Back SA, Riddle A, Hohimer AR. Role of instrumented fetal sheep preparations in defining the pathogenesis of human periventricular white-matter injury. J Child Neurol. 2006;21 (7): 582–589.

  32. 32.

    Stonestreet BS, Oen-Hsiao JM, Petersson KH, et al. Regulation of brain water during acute hyperosmolality in ovine fetuses, lambs, and adults. J Appl Physiol. 2003;94 (4): 1491–1500.

  33. 33.

    Jorgensen PL. Purification and characterization of (Na+ plus K+)-ATPase. 3. Purification from the outer medulla of mammalian kidney after selective removal of membrane components by sodium dodecylsulphate. Biochim Biophys Acta. 1974;356 (1): 36–52.

  34. 34.

    Lo SC, August TR, Liberman UA, et al. Dependence of renal (Na+ + K+)-adenosine triphosphatase activity on thyroid status. J Biol Chem. 1976;251 (24): 7826–7833.

  35. 35.

    Schmitt CA, McDonough AA. Developmental and thyroid hormone regulation of two molecular forms of Na+-K+-ATPase in brain. J Biol Chem. 1986;261 (22): 10439–10444.

  36. 36.

    Fiske C, Subbarow Y. The colorimetric determination of phosphorus. J Biol Chem. 1925;66 (2): 375–400.

  37. 37.

    Mehter NS, Sadowska GB, Malaeb SN, et al. Na+, K+-ATPase activity and subunit isoform protein abundance: effects of antenatal glucocorticoids in the frontal cerebral cortex and renal cortex of ovine fetuses. Reprod Sci. 2009;16 (3): 294–307. Epub 2008 Nov 2011.

  38. 38.

    Tseng YT, Yano N, Rojan A, et al. Ontogeny of phosphoinositide 3-kinase signaling in developing heart: effect of acute beta-adrenergic stimulation. Am J Physiol Heart Circ Physiol. 2005;289 (5): H1834–H1842.

  39. 39.

    Wintour EM. Developmental aspects of the hypothalamic-pituitary-adrenal axis. J Dev Physiol. 1984;6 (3): 291–299.

  40. 40.

    Stonestreet BS, Patlak CS, Pettigrew KD, et al. Ontogeny of blood-brain barrier function in ovine fetuses, lambs, and adults. Am J Physiol. 1996;271 (6 pt 2): R1594–R1601.

  41. 41.

    Duncan AR, Sadowska GB, Stonestreet BS. Ontogeny and the effects of exogenous and endogenous glucocorticoids on tight junction protein expression in ovine cerebral cortices. Brain Res. 2009;1303:15–25.

  42. 42.

    Devarajan P, Benz EJ. Translational regulation of Na-K-ATPase subunit mRNAs by glucocorticoids. Am J Physiol Renal Physiol. 2000;279 (6): F1132–F1138.

  43. 43.

    Malaeb SN, Hovanesian V, Sarasin MD, et al. Effects of maternal antenatal glucocorticoid treatment on apoptosis in the ovine fetal cerebral cortex. J Neurosci Res. 2009;87 (1): 179–189.

  44. 44.

    Dobbing J, Sands J. Comparative aspects of the brain growth spurt. Early Hum Dev. 1979;3 (1): 79–83.

  45. 45.

    McIntosh GH, Baghurst KI, Potter BJ, et al. Foetal brain development in the sheep. Neuropathol Appl Neurobiol. 1979;5 (2): 103–114.

  46. 46.

    Barlow RM. The foetal sheep: morphogenesis of the nervous system and histochemical aspects of myelination. J Comp Neurol. 1969;135 (3): 249–262.

  47. 47.

    Aperia A, Larsson L, Zetterstrom R. Hormonal induction of Na-K-ATPase in developing proximal tubular cells. Am J Physiol. 1981;241 (4): F356–F360.

  48. 48.

    Rane S, Aperia A. Ontogeny of Na-K-ATPase activity in thick ascending limb and of concentrating capacity. Am J Physiol. 1985;249 (5 pt 2): F723–F728.

  49. 49.

    Celsi G, Nishi A, Akusjarvi G, et al. Abundance of Na(+)-K(+)-ATPase mRNA is regulated by glucocorticoid hormones in infant rat kidneys. Am J Physiol. 1991;260 (2 pt 2): F192–F197.

  50. 50.

    Turner AJ, Brown RD, Carlstrom M, et al. Mechanisms of neonatal increase in glomerular filtration rate. Am J Physiol Regul Integr Comp Physiol. 2008;295 (3): R916–R921.

  51. 51.

    Guillery EN, Huss DJ, McDonough AA, et al. Posttranscriptional upregulation of Na(+)-K(+)-ATPase activity in newborn guinea pig renal cortex. Am J Physiol. 1997;273 (2 pt 2): F254–F263.

  52. 52.

    Matthews SG. Antenatal glucocorticoids and the developing brain: mechanisms of action. Semin Neonatol. 2001;6 (4): 309–317.

  53. 53.

    Schinkel AH, Wagenaar E, van Deemter L, et al. Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest. 1995;96 (4): 1698–1705.

  54. 54.

    Hantzis V, Albiston A, Matsacos D, et al. Effect of early glucocorticoid treatment on MR and GR in late gestation ovine kidney. Kidney International. 2002;61 (2): 405–413.

  55. 55.

    Jobe AH, Polk DH, Ervin MG, et al. Preterm betamethasone treatment of fetal sheep: outcome after term delivery. J Soc Gynecol Investig. 1996;3 (5): 250–258.

  56. 56.

    Matthews SG. Antenatal glucocorticoids and programming of the developing CNS. Pediatr Res. 2000;47 (3): 291–300.

  57. 57.

    Rose JC, Kute TE, Winkler L. Glucocorticoid receptors in sheep brain tissues during development. Am J Physiol. 1985;249 (4 pt 1): E345–E349.

  58. 58.

    Richards EM, Hua Y, Keller-Wood M. Pharmacology and physiology of ovine corticosteroid receptors. Neuroendocrinology. 2003;77 (1): 2–14.

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Correspondence to Barbara S. Stonestreet MD.

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Kim, C., Sadowska, G.B., Newton, S.A. et al. Na+,K+-ATPase Activity and Subunit Protein Expression: Ontogeny and Effects of Exogenous and Endogenous Steroids on the Cerebral Cortex and Renal Cortex of Sheep. Reprod. Sci. 18, 359–373 (2011).

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  • brain
  • kidney
  • glucocorticoids
  • Na+,K+