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. 1991 May;87(5):1755–1762. doi: 10.1172/JCI115194

Correction of enhanced Na(+)-H+ exchange of rat small intestinal brush-border membranes in streptozotocin-induced diabetes by insulin or 1,25-dihydroxycholecalciferol.

P K Dudeja 1, R K Wali 1, A Klitzke 1, M D Sitrin 1, T A Brasitus 1
PMCID: PMC295285  PMID: 1850761

Abstract

Diabetes was induced in rats by administration of a single i.p. injection of streptozotocin (50 mg/kg body wt). After 7 d, diabetic rats were further treated with insulin or 1,25-dihydroxycholecalciferol [1,25(OH)2D3] for an additional 5-7 d. Control, diabetic, diabetic + insulin, and diabetic + 1,25(OH)2D3 rats were then killed, their proximal small intestines were removed, and villus-tip epithelial cells were isolated and used to prepare brush-border membrane vesicles. Preparations from each of these groups were then analyzed and compared with respect to their amiloride-sensitive, electroneutral Na(+)-H+ exchange activity, using 22Na uptake as well as acridine orange techniques. The results of these experiments demonstrated that (a) H+ gradient-dependent 22Na uptake as well as Na+ gradient-dependent transmembrane H+ fluxes were significantly increased in diabetic vesicles compared to their control counterparts, (b) kinetic studies demonstrated that this enhanced 22Na uptake in diabetes was a result of increased maximal velocity (Vmax) of this exchanger with no change in apparent affinity (Km) for Na+, (c) serum levels of 1,25(OH)2D3 were significantly lower in diabetic animals compared with their control counterparts; and (d) insulin or 1,25(OH)2D3 treatment restored the Vmax alterations to control values, without any significant changes in Km, concomitant with significantly increasing the serum levels of 1,25(OH)2D3 in diabetic animals. These results indicate that Na(+)-H+ activity is significantly increased in proximal small intestinal luminal membranes of streptozotocin-induced diabetic rats. Moreover, alterations in the serum levels of 1,25(OH)2D3 may, at least in part, explain this enhanced antiporter activity and its correction by insulin.

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Selected References

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  1. Aronson P. S., Nee J., Suhm M. A. Modifier role of internal H+ in activating the Na+-H+ exchanger in renal microvillus membrane vesicles. Nature. 1982 Sep 9;299(5879):161–163. doi: 10.1038/299161a0. [DOI] [PubMed] [Google Scholar]
  2. Aulsebrook K. A. Intestinal transport of glucose and sodium: changes in alloxan diabetes and effects of insulin. Experientia. 1965 Jun 15;21(6):346–347. doi: 10.1007/BF02144708. [DOI] [PubMed] [Google Scholar]
  3. Brasitus T. A., Dudeja P. K., Bolt M. J., Sitrin M. D., Baum C. Dietary triacylglycerol modulates sodium-dependent D-glucose transport, fluidity and fatty acid composition of rat small intestinal brush-border membrane. Biochim Biophys Acta. 1989 Feb 27;979(2):177–186. doi: 10.1016/0005-2736(89)90433-1. [DOI] [PubMed] [Google Scholar]
  4. Brasitus T. A., Dudeja P. K. Correction of abnormal lipid fluidity and composition of rat ileal microvillus membranes in chronic streptozotocin-induced diabetes by insulin therapy. J Biol Chem. 1985 Oct 15;260(23):12405–12409. [PubMed] [Google Scholar]
  5. Brasitus T. A., Dudeja P. K., Eby B., Lau K. Correction by 1-25-dihydroxycholecalciferol of the abnormal fluidity and lipid composition of enterocyte brush border membranes in vitamin D-deprived rats. J Biol Chem. 1986 Dec 15;261(35):16404–16409. [PubMed] [Google Scholar]
  6. Brasitus T. A., Schachter D., Mamouneas T. G. Functional interactions of lipids and proteins in rat intestinal microvillus membranes. Biochemistry. 1979 Sep 18;18(19):4136–4144. doi: 10.1021/bi00586a013. [DOI] [PubMed] [Google Scholar]
  7. Caspary W. F. Increase of active transport of conjugated bile salts in streptozotocin-diabetic rat small intestine. Gut. 1973 Dec;14(12):949–955. doi: 10.1136/gut.14.12.949. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cassano G., Stieger B., Murer H. Na/H- and Cl/OH-exchange in rat jejunal and rat proximal tubular brush border membrane vesicles. Studies with acridine orange. Pflugers Arch. 1984 Mar;400(3):309–317. doi: 10.1007/BF00581565. [DOI] [PubMed] [Google Scholar]
  9. Donowitz M., Wicks J., Cusolito S., Sharp G. W. Cytosol free Ca++ in the regulation of active intestinal Na and Cl transport. Kroc Found Ser. 1984;17:171–189. [PubMed] [Google Scholar]
  10. Dudeja P. K., Foster E. S., Brasitus T. A. Modulation of rat distal colonic brush-border membrane Na+-H+ exchange by dexamethasone: role of lipid fluidity. Biochim Biophys Acta. 1987 Dec 11;905(2):485–493. doi: 10.1016/0005-2736(87)90478-0. [DOI] [PubMed] [Google Scholar]
  11. Dudeja P. K., Foster E. S., Brasitus T. A. Na+-H+ antiporter of rat colonic basolateral membrane vesicles. Am J Physiol. 1989 Oct;257(4 Pt 1):G624–G632. doi: 10.1152/ajpgi.1989.257.4.G624. [DOI] [PubMed] [Google Scholar]
  12. Dudeja P. K., Foster E. S., Brasitus T. A. Regulation of Na+-H+ exchange by transmethylation reactions in rat colonic brush-border membranes. Biochim Biophys Acta. 1986 Jul 10;859(1):61–68. doi: 10.1016/0005-2736(86)90318-4. [DOI] [PubMed] [Google Scholar]
  13. Dudeja P. K., Foster E. S., Dahiya R., Brasitus T. A. Modulation of Na+-H+ exchange by ethinyl estradiol in rat colonic brush-border membrane vesicles. Biochim Biophys Acta. 1987 May 29;899(2):222–228. doi: 10.1016/0005-2736(87)90403-2. [DOI] [PubMed] [Google Scholar]
  14. Dudeja P. K., Wali R. K., Klitzke A., Brasitus T. A. Intestinal D-glucose transport and membrane fluidity along crypt-villus axis of streptozocin-induced diabetic rats. Am J Physiol. 1990 Oct;259(4 Pt 1):G571–G577. doi: 10.1152/ajpgi.1990.259.4.G571. [DOI] [PubMed] [Google Scholar]
  15. Favus M. J., Tembe V., Tanklefsky M. D., Ambrosic K. A., Nellans H. N. Effects of quinacrine on calcium active transport by rat intestinal epithelium. Am J Physiol. 1989 Nov;257(5 Pt 1):G818–G822. doi: 10.1152/ajpgi.1989.257.5.G818. [DOI] [PubMed] [Google Scholar]
  16. Fine L. G., Badie-Dezfooly B., Lowe A. G., Hamzeh A., Wells J., Salehmoghaddam S. Stimulation of Na+/H+ antiport is an early event in hypertrophy of renal proximal tubular cells. Proc Natl Acad Sci U S A. 1985 Mar;82(6):1736–1740. doi: 10.1073/pnas.82.6.1736. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Foster E. S., Dudeja P. K., Brasitus T. A. Na+-H+ exchange in rat colonic brush-border membrane vesicles. Am J Physiol. 1986 Jun;250(6 Pt 1):G781–G787. doi: 10.1152/ajpgi.1986.250.6.G781. [DOI] [PubMed] [Google Scholar]
  18. Fuchs R., Graf J., Peterlik M. Effects of 1 alpha,25-dihydroxycholecalciferol on sodium-ion translocation across chick intestinal brush-border membrane. Biochem J. 1985 Sep 1;230(2):441–449. doi: 10.1042/bj2300441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Ghijsen W. E., De Jong M. D., Van Os C. H. Kinetic properties of Na+/Ca2+ exchange in basolateral plasma membranes of rat small intestine. Biochim Biophys Acta. 1983 Apr 21;730(1):85–94. doi: 10.1016/0005-2736(83)90320-6. [DOI] [PubMed] [Google Scholar]
  20. Ghishan F. K., Borowitz S., Mulberg A. Phosphate transport by jejunal brush border membrane vesicles of the streptozocin-diabetic rat. Diabetes. 1985 Aug;34(8):723–727. doi: 10.2337/diab.34.8.723. [DOI] [PubMed] [Google Scholar]
  21. Grinstein S., Goetz J. D. Control of free cytoplasmic calcium by intracellular pH in rat lymphocytes. Biochim Biophys Acta. 1985 Oct 10;819(2):267–270. doi: 10.1016/0005-2736(85)90183-x. [DOI] [PubMed] [Google Scholar]
  22. Grinstein S., Rothstein A. Mechanisms of regulation of the Na+/H+ exchanger. J Membr Biol. 1986;90(1):1–12. doi: 10.1007/BF01869680. [DOI] [PubMed] [Google Scholar]
  23. Grinstein S., Rotin D., Mason M. J. Na+/H+ exchange and growth factor-induced cytosolic pH changes. Role in cellular proliferation. Biochim Biophys Acta. 1989 Jan 18;988(1):73–97. doi: 10.1016/0304-4157(89)90004-x. [DOI] [PubMed] [Google Scholar]
  24. Gunther R. D., Wright E. M. Na+, Li+, and Cl- transport by brush border membranes from rabbit jejunum. J Membr Biol. 1983;74(2):85–94. doi: 10.1007/BF01870497. [DOI] [PubMed] [Google Scholar]
  25. Harris R. C., Brenner B. M., Seifter J. L. Sodium-hydrogen exchange and glucose transport in renal microvillus membrane vesicles from rats with diabetes mellitus. J Clin Invest. 1986 Mar;77(3):724–733. doi: 10.1172/JCI112367. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Harris R. C., Seifter J. L., Brenner B. M. Adaptation of Na+-H+ exchange in renal microvillus membrane vesicles. Role of dietary protein and uninephrectomy. J Clin Invest. 1984 Dec;74(6):1979–1987. doi: 10.1172/JCI111619. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Hopfer U. Diabetes mellitus: changes in the transport properties of isolated intestinal microvillous membranes. Proc Natl Acad Sci U S A. 1975 Jun;72(6):2027–2031. doi: 10.1073/pnas.72.6.2027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Ives H. E., Yee V. J., Warnock D. G. Mixed type inhibition of the renal Na+/H+ antiporter by Li+ and amiloride. Evidence for a modifier site. J Biol Chem. 1983 Aug 25;258(16):9710–9716. [PubMed] [Google Scholar]
  29. Kinsella J., Cujdik T., Sacktor B. Na+-H+ exchange activity in renal brush border membrane vesicles in response to metabolic acidosis: The role of glucocorticoids. Proc Natl Acad Sci U S A. 1984 Jan;81(2):630–634. doi: 10.1073/pnas.81.2.630. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kinsella J., Sacktor B. Thyroid hormones increase Na+-H+ exchange activity in renal brush border membranes. Proc Natl Acad Sci U S A. 1985 Jun;82(11):3606–3610. doi: 10.1073/pnas.82.11.3606. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Knickelbein R. G., Aronson P. S., Dobbins J. W. Membrane distribution of sodium-hydrogen and chloride-bicarbonate exchangers in crypt and villus cell membranes from rabbit ileum. J Clin Invest. 1988 Dec;82(6):2158–2163. doi: 10.1172/JCI113838. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Knickelbein R., Aronson P. S., Atherton W., Dobbins J. W. Sodium and chloride transport across rabbit ileal brush border. I. Evidence for Na-H exchange. Am J Physiol. 1983 Oct;245(4):G504–G510. doi: 10.1152/ajpgi.1983.245.4.G504. [DOI] [PubMed] [Google Scholar]
  33. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  34. Lal D., Schedl H. P. Intestinal adaptation in diabetes: amino acid absorption. Am J Physiol. 1974 Oct;227(4):827–831. doi: 10.1152/ajplegacy.1974.227.4.827. [DOI] [PubMed] [Google Scholar]
  35. Lee H. C., Forte J. G. A study of H+ transport in gastric microsomal vesicles using fluorescent probes. Biochim Biophys Acta. 1978 Apr 4;508(2):339–356. doi: 10.1016/0005-2736(78)90336-x. [DOI] [PubMed] [Google Scholar]
  36. Lieberherr M., Grosse B., Duchambon P., Drüeke T. A functional cell surface type receptor is required for the early action of 1,25-dihydroxyvitamin D3 on the phosphoinositide metabolism in rat enterocytes. J Biol Chem. 1989 Dec 5;264(34):20403–20406. [PubMed] [Google Scholar]
  37. Manganel M., Turner R. J. Agonist-induced activation of Na+/H+ exchange in rat parotid acinar cells is dependent on calcium but not on protein kinase C. J Biol Chem. 1990 Mar 15;265(8):4284–4289. [PubMed] [Google Scholar]
  38. Miller D. L., Hanson W., Schedl H. P., Osborne J. W. Proliferation rate and transit time of mucosal cells in small intestine of the diabetic rat. Gastroenterology. 1977 Dec;73(6):1326–1332. [PubMed] [Google Scholar]
  39. Moolenaar W. H., Yarden Y., de Laat S. W., Schlessinger J. Epidermal growth factor induces electrically silent Na+ influx in human fibroblasts. J Biol Chem. 1982 Jul 25;257(14):8502–8506. [PubMed] [Google Scholar]
  40. Murer H., Hopfer U., Kinne R. Sodium/proton antiport in brush-border-membrane vesicles isolated from rat small intestine and kidney. Biochem J. 1976 Mar 15;154(3):597–604. [PMC free article] [PubMed] [Google Scholar]
  41. Murer H., Hopfer U., Kinne R. Sodium/proton antiport in brush-border-membrane vesicles isolated from rat small intestine and kidney. Biochem J. 1976 Mar 15;154(3):597–604. [PMC free article] [PubMed] [Google Scholar]
  42. Olsen W. A., Rosenberg I. H. Intestinal transport of sugars and amino acids in diabetic rats. J Clin Invest. 1970 Jan;49(1):96–105. doi: 10.1172/JCI106227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Patel D. G. Rate of insulin infusion with a minipump required to maintain a normoglycemia in diabetic rats. Proc Soc Exp Biol Med. 1983 Jan;172(1):74–78. doi: 10.3181/00379727-172-41529. [DOI] [PubMed] [Google Scholar]
  44. Rajendran V. M., Binder H. J. Characterization of Na-H exchange in apical membrane vesicles of rat colon. J Biol Chem. 1990 May 25;265(15):8408–8414. [PubMed] [Google Scholar]
  45. Ramaswamy K., Harig J. M., Kleinman J. G., Harris M. S., Barry J. A. Sodium-proton exchange in human ileal brush-border membrane vesicles. Biochim Biophys Acta. 1989 Jun 6;981(2):193–199. doi: 10.1016/0005-2736(89)90028-x. [DOI] [PubMed] [Google Scholar]
  46. Reenstra W. W., Warnock D. G., Yee V. J., Forte J. G. Proton gradients in renal cortex brush-border membrane vesicles. Demonstration of a rheogenic proton flux with acridine orange. J Biol Chem. 1981 Nov 25;256(22):11663–11666. [PubMed] [Google Scholar]
  47. Schedl H. P., Wilson H. D. Effects of diabetes on intestinal growth and hexose transport in the rat. Am J Physiol. 1971 Jun;220(6):1739–1745. doi: 10.1152/ajplegacy.1971.220.6.1739. [DOI] [PubMed] [Google Scholar]
  48. Schedl H. P., Wilson H. D. Jejunal sodium transport in the rat: effects of alloxan diabetes. Biochim Biophys Acta. 1974 Oct 29;367(2):225–231. doi: 10.1016/0005-2736(74)90045-5. [DOI] [PubMed] [Google Scholar]
  49. Schneider L. E., Schedl H. P. Diabetes and intestinal calcium absorption in the rat. Am J Physiol. 1972 Dec;223(6):1319–1323. doi: 10.1152/ajplegacy.1972.223.6.1319. [DOI] [PubMed] [Google Scholar]
  50. Schneider L. E., Schedl H. P., McCain T., Haussler M. R. Experimental diabetes reduces circulating 1,25-dihydroxyvitamin D in the rat. Science. 1977 Jun 24;196(4297):1452–1454. doi: 10.1126/science.141098. [DOI] [PubMed] [Google Scholar]
  51. Semrad C. E., Chang E. B. Calcium-mediated cyclic AMP inhibition of Na-H exchange in small intestine. Am J Physiol. 1987 Mar;252(3 Pt 1):C315–C322. doi: 10.1152/ajpcell.1987.252.3.C315. [DOI] [PubMed] [Google Scholar]
  52. Semrad C. E., Cragoe E. J., Jr, Chang E. B. Inhibition of Na/H exchange in avian intestine by atrial natriuretic factor. J Clin Invest. 1990 Aug;86(2):585–591. doi: 10.1172/JCI114748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Tsai C. J., Ives H. E., Alpern R. J., Yee V. J., Warnock D. G., Rector F. C., Jr Increased Vmax for Na+/H+ antiporter activity in proximal tubule brush border vesicles from rabbits with metabolic acidosis. Am J Physiol. 1984 Aug;247(2 Pt 2):F339–F343. doi: 10.1152/ajprenal.1984.247.2.F339. [DOI] [PubMed] [Google Scholar]
  54. Wali R. K., Baum C. L., Sitrin M. D., Brasitus T. A. 1,25(OH)2 vitamin D3 stimulates membrane phosphoinositide turnover, activates protein kinase C, and increases cytosolic calcium in rat colonic epithelium. J Clin Invest. 1990 Apr;85(4):1296–1303. doi: 10.1172/JCI114567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Warnock D. G., Reenstra W. W., Yee V. J. Na+/H+ antiporter of brush border vesicles: studies with acridine orange uptake. Am J Physiol. 1982 Jun;242(6):F733–F739. doi: 10.1152/ajprenal.1982.242.6.F733. [DOI] [PubMed] [Google Scholar]
  56. Weiser M. M. Intestinal epithelial cell surface membrane glycoprotein synthesis. I. An indicator of cellular differentiation. J Biol Chem. 1973 Apr 10;248(7):2536–2541. [PubMed] [Google Scholar]

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