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Cation-chloride cotransporters: Regulation, physiological significance, and role in pathogenesis of arterial hypertension

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Abstract

This review summarizes the data on the functioning of carriers providing electroneutral symport of sodium, potassium, and chloride (Na+,K+,2Cl− cotransport), potassium and chloride (K+,Cl− cotransport), and sodium and chloride (K+,Cl− cotransport) as well as molecular mechanisms of the regulation of these carriers and their physiological significance. We emphasized the involvement of chloride-coupled carriers in the regulation of cell volume and intracellular chloride concentration and novel data on the role of ubiquitous isoform of Na+,K+,2Cl− cotransporter NKCC1 in regulation of vascular smooth muscle contraction and activity of GABAA receptors. Finally, we analyzed the data on activation of NKCC1 in patients with essential hypertension and its role in the long-term maintenance of elevated systemic blood pressure and myogenic response in microcirculatory beds.

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Abbreviations

CCC:

cation-chloride cotransporters

CNS:

central nervous system

GABA:

γ-aminobutyric acid

KCC:

K+,Cl− cotransport

NCC:

Na+,Cl− cotransport

NKCC:

Na+,K+,2Cl− cotransport

OSR1:

oxidative stress response kinase

PVN:

paraventricular nucleus

SMC:

smooth muscle cell

SNS:

sympathetic nervous system

SPAK:

Ste20-related praline-alanine-rich kinase

WNK:

“with no K” lysine kinase

References

  1. Hediger, M. A., Romero, M. F., Peng, J.-B., Rolfs, A., Takanaga, H., and Bruford, E. A. (2004) The ABCs of solute carriers: physiological, pathophysiological and therapeutic implications of human membrane transport protein, Pfluger Arch. Europ. J. Physiol., 447, 465–468.

    CAS  Google Scholar 

  2. Gamba, G. (2005) Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters, Physiol. Rev., 85, 423–493.

    PubMed  CAS  Google Scholar 

  3. Orlov, S. N., and Mongin, A. A. (2007) Salt sensing mechanisms in blood pressure regulation and hypertension, Am. J. Physiol. Heart Circ. Physiol., 293, H2039–H2053.

    PubMed  CAS  Google Scholar 

  4. Markadieu, N., and Delpire, E. (2014) Physiology and pathophysiology of SLC12A1/2 transporters, Pfluger Arch. Europ. J. Physiol., 466, 91–105.

    CAS  Google Scholar 

  5. Garzon-Mudvi, T., Schiapparelli, P., ap Rhys, C., Guerrero-Cazares, H., Smith, C., Kim, D.-H., Kone, L., Farber, H., Lee, D. Y., An, S. S., Levchenko, A., and Quinones-Hinojosa, A. (2012) Regulation of brain tumor dispersal by NKCC1 through a novel role in focal adhesion regulation, PLoS Biol., 10, e1001320.

    Google Scholar 

  6. Chen, Y.-F., Chou, C.-Y., Ellory, J. C., and Shen, M.-R. (2010) The emerging role of KCl cotransport in tumor biology, Am. J. Transl. Res., 2, 345–355.

    PubMed Central  PubMed  CAS  Google Scholar 

  7. Kahle, K. T., Staley, K. J., Nahed, B. V., Gamba, G., Hebert, S. C., Lifton, R. P., and Mount, D. B. (2008) Roles of the cation-chloride cotransporters in neurological disease, Nature Clin. Pract. Neurol., 4, 490–503.

    CAS  Google Scholar 

  8. Loscher, W., Puskarjov, M., and Kaila, K. (2013) Cationchloride cotransporters NKCC1 and KCC2 as potential targets for novel antiepileptic and antiepileptogenic treatments, Neuropharmacology, 69, 62–74.

    PubMed  Google Scholar 

  9. Rust, M. B., Alper, S. L., Rudhard, Y., Shmukler, B. E., Vicente, R., Brugnara, C., Trudel, M., Jentsch, T. J., and Hubner, C. A. (2007) Disruption of erythroid K-Cl cotransporters alters erythrocyte volume and partially rescues erythrocyte dehydration in SAD mice, J. Clin. Investig., 117, 1708–1717.

    PubMed Central  PubMed  CAS  Google Scholar 

  10. Rinehart, J., Gulcicek, E. E., Joiner, C. H., Lifton, R. P., and Gallagher, P. G. (2010) Determinants of erythrocyte hydration, Curr. Opin. Haematol., 17, 191–197.

    CAS  Google Scholar 

  11. Lang, F., and Voelkl, J. (2013) Therapeutic potential of serum and glucocorticoid inducible kinase inhibition, Expert Opin. Investig. Drugs, 22, 701–714.

    PubMed  CAS  Google Scholar 

  12. Gagnon, F., Hamet, P., and Orlov, S. N. (1999) Na+,K+ pump and Na+-coupled ion carriers in isolated mammalian kidney epithelial cells: regulation by protein kinase C, Canad. J. Physiol. Pharmacol., 77, 305–319.

    CAS  Google Scholar 

  13. Orlov, S. N., Resink, T. J., Bernhardt, J., and Buhler, F. R. (1992) Na+-K+ pump and Na+-K+ cotransport in cultured vascular smooth muscle cells from spontaneously hypertensive rats: baseline activity and regulation, J. Hypertens., 10, 733–740.

    PubMed  CAS  Google Scholar 

  14. Smith, J. B., and Smith, L. (1987) Na+/K+/Cl− cotransport in cultured vascular smooth muscle cells: stimulation by angiotensin II and calcium ionophores, inhibition by cyclic AMP and calmodulin antagonists, J. Membr. Biol., 99, 51–63.

    PubMed  CAS  Google Scholar 

  15. Orlov, S. N., Tremblay, J., and Hamet, P. (1996) Cell volume in vascular smooth muscle is regulated by bumetanide-sensitive ion transport, Am. J. Physiol., 270, C1388–C1397.

    PubMed  CAS  Google Scholar 

  16. Adragna, N., White, R. E., Orlov, S. N., and Lauf, P. K. (2000) K-Cl cotransport in vascular smooth muscle and erythrocytes: possible implication in vasodilation, Am. J. Physiol., 278, C381–C390.

    Google Scholar 

  17. Gagnon, F., Orlov, S. N., Tremblay, J., and Hamet, P. (1998) Complete inhibition of Na+,K+,Cl− cotransport in Madin-Darby canine kidney cells by PMA-sensitive protein kinase C, Biochim. Biophys. Acta, 1369, 233–239.

    PubMed  CAS  Google Scholar 

  18. Gagnon, F., Dulin, N. O., Tremblay, J., Hamet, P., and Orlov, S. N. (1999) ATP-induced inhibition of Na+,K+,Cl− cotransport in Madin-Darby canine kidney cells: lack of involvement of known purinoceptor-coupled signaling pathways, J. Membr. Biol., 167, 193–204.

    PubMed  CAS  Google Scholar 

  19. Orlov, S. N., Dulin, N. O., Gagnon, F., Gekle, M., Douglas, J. G., Schwartz, J. H., and Hamet, P. (1999) Purinergic regulation of Na+,K+,Cl− cotransport and MAP kinases is limited to C11-MDCK cells resembling intercalated cells from collecting ducts, J. Membr. Biol., 172, 225–234.

    PubMed  CAS  Google Scholar 

  20. Lytle, C., and Forbush III, B. (1992) The Na-K-Cl cotransport protein of shark rectal gland. II. Regulation by direct phosphorylation, J. Biol. Chem., 267, 25438–25443.

    PubMed  CAS  Google Scholar 

  21. Grubb, B. R., Pace, A. J., Lee, E., Koller, B. H., and Boucher, R. C. (2001) Alterations in airway ion transport in NKCC1-deficient mice, Am. J. Physiol. Cell Physiol., 281, C615–C623.

    Google Scholar 

  22. Lytle, C. (1997) Activation of avian erythrocyte Na-K-Cl cotransport by cell shrinkage, cAMP, fluoride, and calyculin A involves phosphorylation at common sites, J. Biol. Chem., 272, 15069–15077.

    PubMed  CAS  Google Scholar 

  23. Lytle, C. (1998) A volume-sensitive protein kinase regulates the Na-K-Cl cotransporter in duck red blood cells, Am. J. Physiol., 274, C1002–C1010.

    Google Scholar 

  24. Lytle, C., and McManus, T. (2002) Coordinate modulation of Na-K-2Cl cotransport and K-Cl cotransport by cell volume and chloride, Am. J. Physiol. Cell Physiol., 283, C1422–C1431.

    PubMed  CAS  Google Scholar 

  25. Kahle, K. T., Rinehart, J., Ring, A., Gimenez, I., Gamba, G., Hebert, G., and Lifton, R. P. (2006) WNK protein kinase modulate cellular Cl-flux altering the phosphorylation state of the Na-K-Cl and K-Cl cotransporters, Physiology, 21, 326–335.

    PubMed  CAS  Google Scholar 

  26. Dowd, B. F., and Forbush, B. (2003) PASK (proline-alanine-rich STE20-related kinase), a regulatory kinase of the Na-K-Cl cotransporter (NKCK1), J. Biol. Chem., 278, 27347–27353.

    PubMed  CAS  Google Scholar 

  27. Piechotta, K., Lu, J., and Delpire, E. (2002) Cation chloride cotransporters interact with the stress-related kinases Ste20-related proline-alanine-rich kinase (SPAK) and oxidative response 1 (OSR1), J. Biol. Chem., 277, 50812–50819.

    PubMed  CAS  Google Scholar 

  28. Delpire, E., and Austin, T. M. (2010) Kinase regulation of Na+-K+-2Cl− cotransport in primary neurons, J. Physiol. (L), 588, 3365–3373.

    CAS  Google Scholar 

  29. Wilson, F. H., Disse-Nicodeme, S., Choate, K. A., Ishikawa, K., Nelson-Williams, C., Desitter, I., Gunel, M., Milford, D. V., Lipkin, G. W., Achard, J. M., Feely, M. P., Dussil, B., Berland, Y., Unwin, R. J., Mayan, H., Simon, D. B., Farfel, Z., Jeunemaitre, X., and Lifton, R. P. (2001) Human hypertension caused by mutations in WNK kinases, Science, 293, 1107–1112.

    PubMed  CAS  Google Scholar 

  30. Kahle, K. T., Rinehart, J., de los Heros, P., Louvi, A., Meade, P., Vazquez, N., Hebert, S. C., Gamba, G., Gimenez, I., and Lifton, R. P. (2005) WNK3 modulates transport of Cl− in and out of cells: implications for control of cell volume and neuronal excitability, Proc. Natl. Acad. Sci. USA, 102, 16783–16788.

    PubMed Central  PubMed  CAS  Google Scholar 

  31. Rinehart, J., Kahle, K. T., de los Heros, P., Vazquez, N., Meade, P., Wilson, F. H., Hebert, S. C., Gimenez, I., Gamba, G., and Lifton, R. P. (2005) WNK3 kinase is a positive regulator of NKCC2 and NCC, renal cation-Cl− cotransporters required for normal blood pressure homeostasis, Proc. Natl. Acad. Sci. USA, 102, 16777–16782.

    PubMed Central  PubMed  CAS  Google Scholar 

  32. De los Heros, P., Kahle, K. T., Rinehart, J., Bobadilla, N. A., Vazquez, N., San Cristobal, P., Mount, D. B., Lifton, R. P., Hebert, S. C., and Gamba, G. (2006) WNK3 bypasses the tonicity requirement for K-Cl cotransporter activation via phosphatase-dependent pathway, Proc. Natl. Acad. Sci. USA, 103, 1976–1981.

    PubMed Central  Google Scholar 

  33. Delpire, E. (2009) The mammalian family of sterile 2p-like protein kinases, Pfluger Arch. Europ. J. Physiol., 458, 953–967.

    CAS  Google Scholar 

  34. Piechotta, K., Garbarini, N. J., England, R., and Delpire, E. (2003) Characterization of the interaction of the stress kinase SPAK with the Na+-K+-2Cl− cotransporter in the nervous system: evidence for a scaffolding role of the kinase, J. Biol. Chem., 278, 52848–52856.

    PubMed  CAS  Google Scholar 

  35. Gagnon, K. B., England, R., and Delpire, E. (2006) Volume sensitivity of cation-Cl− cotransporters is modulated by the interaction of two kinases: SPAK and WNK4, Am. J. Physiol. Cell Physiol., 290, C134–C142.

    Google Scholar 

  36. Ponce-Coria, J., San-Cristobal, P., Kahle, K. T., Vazquez, N., Pacheco-Alvarez, D., de los Heros, P., Juarez, P., Munoz, E., Michel, G., Bobadilla, N. A., Gimenez, I., Lifton, R. P., Hebert, S. C., and Gamba, G. (2008) Regulation of NKCC2 by a chloride-sensing mechanism involving the WNK3 and SPAK kinases, Proc. Natl. Acad. Sci. USA, 105, 8458–8463.

    PubMed Central  PubMed  CAS  Google Scholar 

  37. Delpire, E., and Gagnon, K. B. (2007) Genome-wide analysis of SPAK/OSR1 binding motifs, Physiol. Genom., 28, 223–231.

    CAS  Google Scholar 

  38. Richardson, C., and Alessi, D. (2008) The regulation of salt transport and blood pressure by the WNK-SPAK/OSR1 signaling pathway, J. Cell Sci., 121, 3293–3304.

    PubMed  CAS  Google Scholar 

  39. Castaneda-Bueno, M., Cervantes-Perez, L. G., Vazquez, N., Uribe, N., Kantesaria, S., Morla, L., Bobadilla, N. A., Alessi, D. R., and Gamba, G. (2012) Alteration of the renal Na+/Cl− cotransporter by angiotensin II is a WNK4-dependent process, Proc. Natl. Acad. Sci. USA, 109, 7929–7934.

    PubMed Central  PubMed  CAS  Google Scholar 

  40. Castaneda-Bueno, M., and Gamba, G. (2012) Mechanisms of sodium-chloride cotransporter modulation by angiotensin II, Curr. Opin. Nephrol. Hypertens., 21, 516–522.

    PubMed  CAS  Google Scholar 

  41. Darman, R. B., and Forbush, B. (2002) A regulatory locus of phosphorylation in the N-terminus of the Na-K-Cl cotransporter, NKCC1, J. Biol. Chem., 277, 37542–37550.

    PubMed  CAS  Google Scholar 

  42. Vitari, A. C., Thastrup, J., Rafigi, F. H., Deak, M., Morrice, N. A., Karlsson, H. K., and Alessi, D. R. (2006) Functional interactions of the SPAK/OSR1 kinases with their upstream activator WNK1 and downstream substrate NKCC1, Biochem. J., 397, 223–231.

    PubMed Central  PubMed  CAS  Google Scholar 

  43. Alvarez-Leefmans, F. J. (2001) Intracellular chloride regulation, in Cell Physiology Source Book. A Molecular Approach (Sperelakis, N., ed.) Academic, San Diego, pp. 301–318.

    Google Scholar 

  44. Chipperfield, A. R., and Harper, A. A. (2001) Chloride in smooth muscle, Progr. Biophys. Mol. Biol., 74, 175–221.

    Google Scholar 

  45. Davis, J. P. L., Chipperfield, A. R., and Harper, A. A. (1993) Accumulation of intracellular chloride by (Na-K-Cl) cotransport in rat arterial smooth muscle is enhanced in deoxycorticosterone acetate (DOCA)/salt hypertension, J. Mol. Cell. Cardiol., 25, 233–237.

    PubMed  CAS  Google Scholar 

  46. Anfinogenova, Y. J., Baskakov, M. B., Kovalev, I. V., Kilin, A. A., Dulin, N. O., and Orlov, S. N. (2004) Cell-volume-dependent vascular smooth muscle contraction: role of Na+,K+,2Cl− cotransport, intracellular Cl− and L-type Ca2+ channels, Pflug. Arch., 449, 42–55.

    CAS  Google Scholar 

  47. Barthelmebs, M., Stephan, D., Fontaine, C., Grima, M., and Imbs, J. L. (1994) Vascular effects of loop diuretics: an in vivo and in vitro study in the rat, Naunyn-Schmiedebergs Arch. Pharmacol., 349, 209–216.

    PubMed  CAS  Google Scholar 

  48. Lavallee, S. L., Iwamoto, L. M., Claybaugh, J. R., Dressel, M. V., Sato, A. K., and Nakamura, K. T. (1997) Furosemide-induced airway relaxation in guinea pigs: relation to Na-K-2Cl cotransport function, Am. J. Physiol., 273, L211–L216.

    Google Scholar 

  49. Tian, R., Aalkjaer, C., and Andreasen, F. (1990) Mechanisms behind the relaxing effect of furosemide on the isolated rabbit ear artery, Pharmacol. Toxicol., 67, 406–410.

    PubMed  CAS  Google Scholar 

  50. Kovalev, I. V., Baskakov, M. B., Anfinogenova, Y. J., Borodin, Y. L., Kilin, A. A., Minochenko, I. L., Popov, A. G., Kapilevich, L. V., Medvedev, M. A., and Orlov, S. N. (2003) Effect of Na+,K+,2Cl− cotransport inhibitor bumetanide on electrical and contractile activity of smooth muscle cells in guinea pig ureter, Byul. Eksp. Biol. Med., 136, 145–149.

    CAS  Google Scholar 

  51. Kovalev, I. V., Baskakov, M. B., Medvedev, M. A., Minochenko, I. L., Kilin, A. A., Anfinogenova, Y. J., Borodin, I. V., Gusakova, S. V., Popov, A. G., Kapilevich, L. V., and Orlov, S. N. (2008) Na+,K+,2Cl− cotransport and chloride permeability of the cell membrane in mezaton and histamine regulation of electrical and contractile activity in smooth muscle cells from the guinea pig ureter, Ross. Fiziol. Zh., 93, 306–317.

    Google Scholar 

  52. Stanke, F., Devillier, P., Breant, D., Chavanon, O., Sessa, C., Bricca, G., and Bessard, G. (1998) Furosemide inhibits angiotensin II-induced contraction on human vascular smooth muscle, Brit. J. Clin. Pharmacol., 46, 571–575.

    CAS  Google Scholar 

  53. Stanke-Labesque, F., Craciwski, J. L., Bedouch, P., Chavanon, O., Magne, J. L., Bessard, G., and Devillier, P. (2000) Furosemide inhibits thromboxane A2-induced contraction in isolated human internal artery and saphenous vein, J. Cardiovasc. Pharmacol., 35, 531–537.

    PubMed  CAS  Google Scholar 

  54. Wang, X., Breaks, J., Loutzenhiser, K., and Loutzenhiser, R. (2007) Effects of inhibition of the Na+/K+/2Cl− cotransporter on myogenic and angiotensin II responses of the rat afferent arteriole, Am. J. Physiol. Renal Physiol., 292, F999–F1006.

    PubMed  CAS  Google Scholar 

  55. Mozhayeva, M. G., and Bagrov, Y. Y. (1995) The inhibitory effects of furosemide on Ca2+ influx pathways associated with oxytocin-induced contractions of rat myometrium, Gen. Physiol. Biophys., 14, 427–436.

    PubMed  CAS  Google Scholar 

  56. Mozhayeva, M. G., Bagrov, Y. Y., Ostretsova, I. B., and Gillespie, J. I. (1994) The effect of furosemide on oxytocin-induced contractions of the rat myometrium, Exp. Physiol., 79, 661–667.

    PubMed  CAS  Google Scholar 

  57. Akar, F., Skinner, E., Klein, J. D., Jena, M., Paul, R. J., and O’Neill, W. C. (1999) Vasoconstrictors and nitrovasodilators reciprocally regulate the Na+-K+-2Cl− cotransporter in rat aorta, Am. J. Physiol., 276, C1383–C1390.

    PubMed  CAS  Google Scholar 

  58. Garg, P., Martin, C., Elms, S. C., Gordon, F. J., Wall, S. M., Garland, C. J., Sutliff, R. L., and O’Neill, W. C. (2007) Effect of the Na-K-2Cl cotransporter NKCC1 on systematic blood pressure and smooth muscle tone, Am. J. Physiol. Heart Circ. Physiol., 292, H2100–H2105.

    Google Scholar 

  59. Palacios, J., Espinoza, F., Munita, C., Cifuentes, F., and Michea, L. (2006) Na+-K+-2Cl− cotransporter is implicated in gender differences in the response of the rat aorta to phenylephrine, Brit. J. Pharmacol., 148, 964–972.

    CAS  Google Scholar 

  60. Koltsova, S. V., Maximov, G. V., Kotelevtsev, S. V., Lavoie, J. L., Tremblay, J., Grygorczyk, R., Hamet, P., and Orlov, S. N. (2009) Myogenic tome in mouse mesenteric arteries: evidence for P2Y receptor-mediated, Na+,K+,2Cl− cotransport-dependent signaling, Purinergic Signaling, 5, 343–349.

    CAS  Google Scholar 

  61. Davis, M. J., and Hill, M. A. (1999) Signaling mechanisms underlying the vascular myogenic response, Physiol. Rev., 79, 387–423.

    PubMed  CAS  Google Scholar 

  62. Hill, M. A., Davis, M. J., Meininger, G. A., Potocnik, S. J., and Murphy, T. V. (2006) Arteriolar myogenic signaling mechanisms: implications for local vascular functions, Clin. Hemorheol. Microcirc., 34, 67–79.

    PubMed  Google Scholar 

  63. Schubert, R., and Mulvany, M. J. (1999) The myogenic response: established facts and attractive hypothesis, Clin. Sci., 96, 313–326.

    PubMed  CAS  Google Scholar 

  64. Koltsova, S. V., Kotelevtsev, S. V., Tremblay, J., Hamet, P., and Orlov, S. N. (2009) Excitation-contraction coupling in resistant mesenteric arteries: evidence for NKCC1-mediated pathway, Biochem. Biophys. Res. Commun., 379, 1080–1083.

    PubMed  CAS  Google Scholar 

  65. Lang, F., Busch, G., Ritter, M., Volkl, H., Waldegger, S., Gulbins, E., and Haussinger, D. (1998) Functional significance of cell volume regulatory mechanisms, Physiol. Rev., 78, 247–306.

    PubMed  CAS  Google Scholar 

  66. Mongin, A. A., and Orlov, S. N. (2001) Mechanisms of cell volume regulation and possible nature of the cell volume sensor, Pathophysiology, 8, 77–88.

    PubMed  CAS  Google Scholar 

  67. Orlov, S. N., Pokudin, N. I., Kotelevtsev, Yu. V., and Gulak, P. V. (1989) Volume-dependent regulation of ion transport and membrane phosphorylation in human and rat erythrocytes, J. Membr. Biol., 107, 105–117.

    PubMed  CAS  Google Scholar 

  68. Adragna, N., Di Fulvio, M., and Lauf, P. K. (2004) Regulation of K-Cl cotransport: from function to genes, J. Membr. Biol., 201, 109–137.

    PubMed  CAS  Google Scholar 

  69. Orlov, S. N. (1994) Ion transport across erythrocyte membrane: mechanisms and volume-dependent regulation, Sov. Sci. Rev. F. Physiol. Gen. Biol., 8, 1–48.

    Google Scholar 

  70. Koltsova, S. V., Akimova, O. A., Orlov, S. N., and Dulin, N. O. (2013) Both Na+/K+ pump and Na+,K+,2Cl− cotransport contribute to cell volume control in human lung fibroblasts, Byul. Sib. Med., 12, 42.

    Google Scholar 

  71. Hoffmann, E. K., Lambert, I. H., and Pedersen, S. F. (2009) Physiology of cell volume regulation in vertebrates, Physiol. Rev., 89, 193–277.

    PubMed  CAS  Google Scholar 

  72. Orlov, S. N., Platonova, A. A., Hamet, P., and Grygorczyk, R. (2013) Cell volume and monovalent ion transporters: their role in the triggering and progression of the cell death machinery, Am. J. Physiol. Cell Physiol., 305, C361–C372.

    PubMed  CAS  Google Scholar 

  73. O’Shaughnessy, K. M., and Karet, F. E. (2006) Salt handling in hypertension, Ann. Rev. Nutr., 26, 343–365.

    Google Scholar 

  74. Balu, S., and Thomas, J. (2006) Incremental expenditure of treating hypertension in the United States, Am. J. Hypertens., 19, 810–816.

    PubMed  Google Scholar 

  75. Guyton, A. C. (1980) Arterial Pressure and Hypertension, WB Saunders Co, Philadelphia.

    Google Scholar 

  76. Postnov, Y. V., and Orlov, S. N. (1987) Primary Hypertension as a Cell Membrane Pathology [in Russian], Meditsina, Moscow.

    Google Scholar 

  77. Lifton, R. P., Gharavi, A. G., and Geller, D. S. (2001) Molecular mechanisms of human hypertension, Cell, 104, 545–556.

    PubMed  CAS  Google Scholar 

  78. Lifton, R. P. (2005) Genetic dissection of human blood pressure variation: common pathways from rare phenotypes, Harvey Lectures, 100, 71–101.

    Google Scholar 

  79. Guyton, A. C. (1991) Blood pressure control — special role of the kidney and body fluids, Science, 252, 1813–1816.

    PubMed  CAS  Google Scholar 

  80. Simon, D. B., Karet, F. E., Hamdan, J. M., Di Pietro, A., Sanjad, S. A., and Lifton, R. P. (1996) Bartter’s syndrome, hypokalemic alkalosis with hypercalciuria, is caused by mutation of Na-K-2Cl cotransporter NKCC2, Nature Genet., 13, 183–188.

    PubMed  CAS  Google Scholar 

  81. Simon, D. B., Nelson-Williams, C., Bia, J., Ellison, D., Karet, F. E., Molina, A. M., Vaara, I., Iwata, F., Cushner, M., Koolen, M., Gainza, F. J., Gitelman, H. J., and Lifton, R. P. (1996) Gitelman’s variant of Bartter’s syndrome, inherited hypokalemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter, Nature Genet., 12, 24–30.

    PubMed  CAS  Google Scholar 

  82. Hamet, P., Pausova, Z., Adarichev, V., Adaricheva, K., and Tremblay, J. (1998) Hypertension: genes and environment, J. Hypertens., 16, 397–418.

    PubMed  CAS  Google Scholar 

  83. Pickering, G. W. (1964) Systematic arterial pressure, in Circulation of the Blood. Men and Ideas (Fishman, A. P., et al., eds.) London, pp. 487–541.

    Google Scholar 

  84. Jones, A. W. (1973) Altered ion transport in vascular smooth muscle from spontaneously hypertensive rats. Influence of aldosterone, norepinephrine and angiotensin, Circ. Res., 33, 563–572.

    PubMed  CAS  Google Scholar 

  85. Postnov, Yu. V., Orlov, S. N., Shevchenko, A. S., and Adler, A. M. (1977) Altered sodium permeability, calcium binding and Na-K-ATPase activity in the red blood cell membrane in essential hypertension, Pflug. Arch. Europ. J. Physiol., 371, 263–269.

    CAS  Google Scholar 

  86. Postnov, Yu. V., and Orlov, S. N. (1985) Ion transport across plasma membrane in primary hypertension, Physiol. Rev., 65, 904–945.

    PubMed  CAS  Google Scholar 

  87. Orlov, S. N., Adragna, N., Adarichev, V. A., and Hamet, P. (1999) Genetic and biochemical determinants of abnormal monovalent ion transport in primary hypertension, Am. J. Physiol., 276, C511–C536.

    Google Scholar 

  88. Garay, R. P., and Alda, O. (2007) What can we learn from erythrocyte Na-K-Cl cotransporter NKCC1 in human hypertension, Pathophysiology, 14, 167–170.

    PubMed  CAS  Google Scholar 

  89. Orlov, S. N., Tremblay, J., and Hamet, P. (2010) NKCC1 and hypertension: a novel therapeutic target involved in regulation of vascular tone and renal function, Curr. Opin. Nephrol. Hypertens., 19, 163–168.

    PubMed  CAS  Google Scholar 

  90. Orlov, S. N., Koltsova, S. V., Tremblay, J., Baskakov, M. B., and Hamet, P. (2012) NKCC1 and hypertension: role in the regulation of vascular smooth muscle contractions and myogenic tone, Ann. Med., 44, S111–S118.

    PubMed  CAS  Google Scholar 

  91. Bianchi, G., Ferrari, P., Trizio, P., Ferrandi, M., Torielli, L., Barber, B. R., and Polli, E. (1985) Red blood cell abnormalities and spontaneous hypertension in rats. A genetically determined link, Hypertension, 7, 319–325.

    PubMed  CAS  Google Scholar 

  92. Kotelevtsev, Yu. V., Orlov, S. N., Pokudin, N. I., Agnaev, V. M., and Postnov, Yu. V. (1987) Genetic analysis of inheritance of Na+,K+ cotransport, calcium level in erythrocytes and blood pressure in F2 hybrids of spontaneously hypertensive and normotensive rats, Byul. Eksp. Biol. Med., 103, 456–458.

    CAS  Google Scholar 

  93. Flagella, M., Clarke, L. L., Miller, M. L., Erway, L. C., Giannella, R. A., Andriga, A., Gawenis, L. R., Kramer, J., Duffy, J. J., Doetschman, T., Lorenz, J. N., Yamoah, E. N., Cardell, E. L., and Shull, G. E. (1999) Mice lacking the basolateral Na-K-2Cl cotransporter have impaired epithelial chloride secretion and are profoundly deaf, J. Biol. Chem., 274, 26946–26955.

    PubMed  CAS  Google Scholar 

  94. Meyer, J. W., Flagella, M., Sutliff, R. L., Lorenz, J. N., Nieman, M. L., Weber, G. S., Paul, R. J., and Shull, G. E. (2002) Decreased blood pressure and vascular smooth muscle tone in mice lacking basolateral Na+-K+-2Cl− cotransporter, Am. J. Physiol., 283, H1846–H1855.

    CAS  Google Scholar 

  95. Wall, S. M., Knepper, M. A., Hassel, K. A., Fischer, M. P., Shodeinde, A., Shin, W., Pham, T. D., Meyer, J. W., Lorenz, J. N., Beierwaltes, W. H., Dietz, J. R., Shull, G. E., and Kim, Y.-H. (2006) Hypotension in NKCC1 null mice: role of the kidney, Am. J. Physiol. Renal Physiol., 290, F409–F416.

    Google Scholar 

  96. Kim, S. M., Eisner, C., Faulhaber-Walter, R., Mizel, D., Wall, S. M., Briggs, J. P., and Schnermann, J. (2008) Salt sensitivity of blood pressure in NKCC1-deficient mice, Am. J. Physiol. Renal Physiol., 295, F1230–F1238.

    Google Scholar 

  97. Lee, H.-A., Baek, I., Seok, Y. M., Yang, E., Cho, H.-M., Lee, D.-Y., Hong, S. H., and Kim, I. K. (2010) Promoter hypomethylation upregulates Na+-K+-2Cl− cotransporter 1 in spontaneously hypertensive rats, Biochem. Biophys. Res. Commun., 396, 252–257.

    PubMed  CAS  Google Scholar 

  98. Cho, H.-M., Lee, H.-A., Kim, H. Y., Han, H. S., and Kim, I. K. (2011) Expression of Na+,K+-2Cl− cotransporter is epigenetically regulated during postnatal development of hypertension, Am. J. Hypertens., 12, 1286–1293.

    Google Scholar 

  99. Mancia, G., Grassi, G., Giannattasio, C., and Seravalle, G. (1999) Sympathetic activation in the pathogenesis of hypertension and progression of organ damage, Hypertension, 34, 724–728.

    PubMed  CAS  Google Scholar 

  100. Schlaich, M. P., Lambert, E., Kaye, D. M., Krozowski, Z., Campbell, D. J., Lambert, G., Hastings, J., Aggarwal, A., and Esler, M. D. (2004) Sympathetic augmentation in hypertension: role of nerve firing, norepinephrine reuptake, and angiotensin neuromodulation, Hypertension, 43, 169–175.

    PubMed  CAS  Google Scholar 

  101. Huang, B. S., Amin, M. S., and Leenen, F. H. H. (2006) The central role of the brain in salt-sensitive hypertension, Curr. Opin. Cardiol., 21, 295–394.

    PubMed  Google Scholar 

  102. Leenen, F. H. H. (2010) The central role of the brain aldosterone-“ouabain” pathway in salt-sensitive hypertension, Biochim. Biophys. Acta, 1802, 1132–1139.

    PubMed  CAS  Google Scholar 

  103. Judy, W. V., Watanabe, A. M., Henry, P. D., Besch, H. R., Murphy, W. R., and Hockel, G. M. (1976) Sympathetic nerve activity: role in regulation of blood pressure in the spontaneously hypertensive rats, Circ. Res., 38, 21–29.

    PubMed  CAS  Google Scholar 

  104. Pyner, S., and Coote, J. H. (2000) Identification of branching paraventricular neurons of the hypothalamus that project to the rostroventrolateral medulla and spinal cord, Neuroscience, 100, 549–556.

    PubMed  CAS  Google Scholar 

  105. Allen, A. M. (2002) Inhibition of the hypothalamic paraventricular nucleus in spontaneously hypertensive rats dramatically reduces sympathetic vasomotor tone, Hypertension, 39, 275–280.

    PubMed  CAS  Google Scholar 

  106. Li, D. P., and Pan, H. L. (2007) Glutamatergic inputs in the hypothalamic paraventricular nucleus maintain sympathetic vasomotor tone in hypertension, Hypertension, 49, 916–925.

    PubMed  CAS  Google Scholar 

  107. Li, D. P., and Pan, H. L. (2007) Role of GABAA and GABAB receptors in paraventricular nucleus in control sympathetic vasomotor tone in hypertension, J. Pharmacol. Exp. Ther., 320, 615–626.

    PubMed  CAS  Google Scholar 

  108. Li, D. P., and Pan, H. L. (2006) Plasticity of GABAergic control of hypothalamic presympathetic neurons in hypertension, Am. J. Physiol. Heart Circ. Physiol., 290, H1110–H1119.

    PubMed  CAS  Google Scholar 

  109. Ye, Z.-Y., Li, D.-P., Byun, H. S., Li, L., and Pan, H.-L. (2012) NKCC1 upregulation disrupts chloride homeostasis in the hypothalamus and increases neuronal-sympathetic drive in hypertension, J. Neurosci., 32, 8560–8568.

    PubMed Central  PubMed  CAS  Google Scholar 

  110. Jiang, G., Cobbs, S., Klein, J. D., and O’Neill, W. C. (2003) Aldosterone regulates the Na-K-Cl cotransporter in vascular smooth muscle, Hypertension, 41, 1131–1135.

    PubMed  CAS  Google Scholar 

  111. Orlov, S. N., Li, J.-M., Tremblay, J., and Hamet, P. (1995) Genes of intracellular calcium metabolism and blood pressure control in primary hypertension, Semin. Nephrol., 15, 569–592.

    PubMed  CAS  Google Scholar 

  112. Hamet, P., Orlov, S. N., and Tremblay, J. (1995) Intracellular signaling mechanisms in hypertension, in Hypertension: Pathophysiology, Diagnosis, and Treatment (Laragh, J. H., et al., eds.) Raven Press, New York, pp. 575–608.

    Google Scholar 

  113. Kahle, K. T., Rinehart, J., Giebisch, G., Gamba, G., Hebert, S. C., and Lifton, R. P. (2008) A novel protein kinase signaling pathway essential for blood pressure regulation in humans, Trends Endocrinol. Metab., 19, 91–95.

    PubMed  CAS  Google Scholar 

  114. Susa, K., Kita, S., Iwamoto, T., Yang, S.-S., Lin, S.-H., Ohta, A., Sohara, E., Rai, T., Sasaki, S., Alessi, D. R., and Uchida, S. (2012) Effect of heterozygous deletion of WNK1 on the WNK-OSR1/SPAK-NCC/NKCC1/NKCC2 signal cascade in the kidney and blood vessels, Clin. Exp. Nephrol., 16, 530–538.

    PubMed  CAS  Google Scholar 

  115. Rafigi, F. H., Zuber, A. M., Glover, M., Richardson, C., Fleming, S., Jovanovic, A., O’Shaughnessy, K. M., and Alessi, D. R. (2010) Role of the WNK-activated SPAK kinase in regulating blood pressure, EMBO Mol. Med., 2, 63–75.

    Google Scholar 

  116. Bergaya, S., Faure, S., Baudrie, V., Rio, M., Escoubet, B., Bonnin, P., Henrion, D., Loirand, G., Achard, J. M., Jeunemaitre, X., and Hadchouel, J. (2011) WNK1 regulates vasoconstriction and blood pressure response to α1-adrenergic stimulation in mice, Hypertension, 58, 439–445.

    PubMed  CAS  Google Scholar 

  117. Yang, S.-S., Lo, Y.-F., Wu, C.-C., Lin, S.-W., Yeh, C.-J., Chu, P., Sytwu, H.-K., Uchida, S., Sasaki, S., and Lin, S.-H. (2010) SPAK-knockout mice manifest Gitelman syndrome and impaired vasoconstriction, J. Am. Soc. Nephrol., 21, 1868–1877.

    PubMed Central  PubMed  CAS  Google Scholar 

  118. Janardhan, V., and Qureshi, A. I. (2004) Mechanisms of ischemic brain injury, Curr. Cardiol. Rep., 6, 117–123.

    PubMed  Google Scholar 

  119. Folkow, B. (2010) Cardiovascular “remodeling” in rat and human: time axis, extent, and in vivo relevance, Physiology, 25, 264–265.

    PubMed  Google Scholar 

  120. Loutzenhiser, R., Griffin, K., Williamson, G., and Bidani, A. (2006) Renal autoregulation: new perspectives regarding the protective and regulatory roles of the underlying mechanisms, Am. J. Physiol. Regul. Integr. Compar. Physiol., 290, R1153–R1167.

    CAS  Google Scholar 

  121. Liu, Y., and Gutterman, D. D. (2009) Vascular control in humans: focus on the coronary microcirculation, Basic Res. Cardiol., 104, 211–227.

    PubMed Central  PubMed  Google Scholar 

  122. Bidani, A., Griffin, K. A., Williamson, G., Wang, X., and Loutzenhiser, R. (2009) Protective importance of the myogenic response in the renal circulation, Hypertension, 54, 393–398.

    PubMed Central  PubMed  CAS  Google Scholar 

  123. Nathan, S., Pepine, C. J., and Bakris, G. L. (2005) Calcium antagonists: effects on cardio-renal risk in hypertensive patients, Hypertension, 46, 637–642.

    PubMed  CAS  Google Scholar 

  124. Griffin, K. A., Picken, M. M., Bakris, G. L., and Bidani, A. K. (1999) Class differences in the effects of calcium channel blockers in the rat remnant kidney model, Kidney Int., 55, 1849–1860.

    PubMed  CAS  Google Scholar 

  125. Bakris, G. L., Toto, R. D., McCullough, P. A., Rocha, R., Purkayastha, D., and Davis, P. (2008) Effect of different ACE inhibitor combinations on albuminuria: results of the GUARD study, Kidney Int., 73, 1303–1309.

    PubMed  CAS  Google Scholar 

  126. Shibata, M. C., Leon, H., Chatterley, T., Dorgan, M., and Vandermeer, B. (2010) Do calcium channel blockers increase the diagnosis of heart failure with hypertension? Am. J. Cardiol., 106, 228–235.

    PubMed  CAS  Google Scholar 

  127. Hansen, P. B., Jensen, B. L., Andreasen, D., and Scott, O. (2001) Differential expression of T- and L-type voltage-dependent calcium channels in renal resistance vessels, Circ. Res., 89, 630–638.

    PubMed  CAS  Google Scholar 

  128. Loutzenhiser, R., and Epstein, M. (1990) The renal hemodynamic effects of calcium antagonists, in Calcium Antagonists and the Kidney (Epstein, M., et al., eds.) Hanley & Belfus, Inc., Philadelphia, pp. 33–74.

    Google Scholar 

  129. Hayashi, K., Homma, K., Wakino, S., Tokuyama, H., Sugano, N., Saruta, T., and Itoh, H. (2010) T-Type channel blockage as a determinant of kidney protection, Keio J. Med., 59, 84–95.

    PubMed  CAS  Google Scholar 

  130. Inscho, E. W., Cook, A. K., Imig, J. D., Vial, C., and Evans, R. J. (2003) Physiological role for P2X1 receptors in renal microvascular autoregulatory behavior, J. Clin. Investig., 112, 1895–1905.

    PubMed Central  PubMed  CAS  Google Scholar 

  131. Orlov, S. N. (2005) Decreased Na+,K+,Cl− cotransport and salt retention in Blacks: a provocative hypothesis, J. Hypertens., 23, 1929–1930.

    PubMed  CAS  Google Scholar 

  132. Orlov, S. N., Gossard, F., Pausova, Z., Akimova, O. A., Tremblay, J., Grim, C. E., Kotchen, J. M., Kotchen, T. A., Gaudet, D., Cowley, A., and Hamet, P. (2010) Decreased NKCC1 activity in erythrocytes from African-Americans with hypertension and dyslipidemia, Am. J. Hypertens., 23, 321–326.

    PubMed Central  PubMed  CAS  Google Scholar 

  133. Khodorov, B. (2004) Glutamate-induced deregulation of calcium homeostasis and mitochondrial dysfunction in mammalian central neurons, Progr. Biophys. Mol. Biol., 86, 279–351.

    CAS  Google Scholar 

  134. Mongin, A. A. (2007) Disruption of ionic and cell volume homeostasis in cerebral ischemia: the perfect storm, Pathophysiology, 14, 183–193.

    PubMed Central  PubMed  CAS  Google Scholar 

  135. Su, G., Kintner, D. B., and Sun, D. (2002) Contribution of Na+,K+,Cl− cotransporter to high [K+]o-induced swelling and EAA release is astrocytes, Am. J. Physiol. Cell Physiol., 282, C1136–C1146.

    PubMed  CAS  Google Scholar 

  136. Busse, S., Breder, J., Dinkel, K., Reymann, K. G., and Schroder, U. H. (2005) Inhibitors of cation-chloride-cotransporters affect hypoxic/hypoglycemic injury in hyppocampal slices, Brain Res., 194, 116–121.

    Google Scholar 

  137. Su, G., Kintner, D. B., Flagella, M., Shull, G. E., and Sun, D. (2002) Astrocytes from Na+,K+,Cl− cotransporter-null mice exhibit absence of swelling and decrease in EAA release, Am. J. Physiol. Cell Physiol., 282, C1147–C1160.

    PubMed  CAS  Google Scholar 

  138. Koltsova, S. V., Luneva, O. G., Lavoie, J. L., Tremblay, J., Maksimov, G. V., Hamet, P., and Orlov, S. N. (2009) HCO3-dependent impact of Na+,K+,2Cl− cotransport in vascular smooth muscle excitation-contraction coupling, Cell. Physiol. Biochem., 23, 407–414.

    PubMed  CAS  Google Scholar 

  139. Williams, R. S., and Benjamin, I. J. (2000) Protective responses in the ischemic myocardium, J. Clin. Investig., 106, 813–818.

    PubMed Central  PubMed  CAS  Google Scholar 

  140. Hannaert, P., Alvarez-Guerra, M., Pirot, D., Nazaret, C., and Garay, R. P. (2002) Rat NKCC2/NKCC1 cotransport selectivity for loop diuretic drugs, Naunyn-Schmiedebergs Arch. Pharmacol., 365, 193–199.

    PubMed  CAS  Google Scholar 

  141. Delpire, E., Lu, J., England, R., Dull, C., and Thorne, T. (1999) Deafness and imbalance associated with inactivation of the secretory Na-K-2Cl cotransporter, Nature Genet., 22, 192–195.

    PubMed  CAS  Google Scholar 

  142. Lang, F., Vallon, V., Knipper, M., and Wangemann, P. (2007) Functional significance of channels and transporters expressed in the inner ear and kidney, Am. J. Physiol. Cell Physiol., 293, C1187–C1208.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Faculty of Biology, Lomonosov Moscow State University, Vorob’evy Gory 1/2, 119991, Moscow, Russia

    S. N. Orlov & S. V. Koltsova

  2. Tomsk State University, pr. Lenina 36, 634050, Tomsk, Russia

    S. N. Orlov & L. V. Kapilevich

  3. Siberian State Medical University, Moskovskii Trakt 2, 634050, Tomsk, Russia

    L. V. Kapilevich & S. V. Gusakova

  4. University of Chicago, Chicago, IL, 600637, USA

    N. O. Dulin

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  1. S. N. Orlov
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Original Russian Text © S. N. Orlov, S. V. Koltsova, L. V. Kapilevich, N. O. Dulin, S. V. Gusakova, 2014, published in Uspekhi Biologicheskoi Khimii, 2014, Vol. 54, pp. 267–298.

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Orlov, S.N., Koltsova, S.V., Kapilevich, L.V. et al. Cation-chloride cotransporters: Regulation, physiological significance, and role in pathogenesis of arterial hypertension. Biochemistry Moscow 79, 1546–1561 (2014). https://doi.org/10.1134/S0006297914130070

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