Роль почек в поддержании кальциевого и магниевого гомеостаза и при его нарушениях (Часть I)

Обзор посвящен проблеме кальциевого и магниевого гомеостаза и его регуляции в организме человека. С учетом последних достижений молекулярной биологии рассматривается процесс пассивного и активного переноса Ca2+ и Mg2+ в различных органах, сложные процессы регуляции их кишечной абсорбции, костной минерализации, передвижения в различных отделах почки. Обсуждается роль клаудинов в обеспечении транспорта двухвалентных катионов в толстом восходящем отделе петли Генле. Рассматриваются особенности топологи клаудинов, обусловливающие функционирование плотных межклеточных контактов в канальцах почек и их значение для процесса парацеллюлярной реабсорбции Ca2+ и Mg2+. Описывается роль каналов семейства TRP в реабсорбции Ca2+ и Mg2+ в дистальных извитых канальцах. Подчеркивается особая роль каналов TRPV5 и TRPV6 в активном трансцеллюлярном переносе этих катионов, что имеет важное значение в регуляции кальциевого и магниевого гомеостаза. Приводятся современные взгляды на топологию и функциональное значение кальций-чувствительных рецепторов, локализованных в паращитовидных железах и нефроне, в регуляции внеклеточного уровня двухвалентных катионов. Отмечается появление агонистов и антагонистов кальций-чувствительных рецепторов и их потенциальная роль в коррекции нарушений кальциевого обмена. Обсуждаются вопросы регуляции почечного транспорта Ca2+ и Mg2+.

гомеостаз кальция и магния, почечный транспорт, клаудины, каналы семейства TRP, кальций-чувствительный рецептор, calcium and magnesium homeostasis, renal transport, claudine, TRP family channels, calcium-sensitive receptor

1. Robertson W.G., Marshall R.W. Calcium measurements in serum and plasma - Total and ionized. CRC Crit. Rev. Clin. Lab. Sci. 1979; 11: 271-304.

2. Брюханов В.М., Зверев Я.Ф. Гомеостаз кальция и магния в норме и при патологии. Барнаул, ИП Колмогоров И.А., 2014; 187 c.

3. Blaine J., Chonchol M., Levi M. Renal control of calcium, phosphate, and magnesium homeostasis. Clin. J. Am. Soc. Nephrol. 2015; 10: 1257-1272.

4. Dimke H., Hoenderop J.G., Bindels R.J. Hereditary tubular transport disorders: implica-tions for renal handling of Ca2+ and Mg2+. Clin. Sci. 2010; 118: 1-18.

5. Riccardi D, Brown E.M. Physiology and pathophysiology of the calcium-sensing receptor in the kidney. Am. J. Physiol. Renal Physiol. 2010; 298 (3): F485-F499.

6. Peacock M. Calcium metabolism in health and disease. CJASN. 2010; (5 Suppl): S23-S30.

7. Miller R.T. Control of renal calcium, phosphate, electrolyte, and water excretion by the calcium-sensing receptor. Best Practice & Res Clin. Endocrinol. & Metabolism. 2013; 27: 345:358.

8. Na T., Peng J-B. TRPV5: A Ca2+ channel for the fine-tuning of Ca2+ reabsorption. In: Mammalian Transient Receptor Potential (TRP) Cation Channels. Nilius B., Flockerzi V. eds. Handbook of Experimental Pharmacology 222. Springer-Verlag. Berlin Heidelberg. 2014; P. 322-357.

9. Bronner F., Pansu D. Nutritional aspects of calcium absorption. J. Nutr. 1999; 129: 9-12.

10. McCormick CC. Passive diffusion does not play a major role in the absorption of dietary calcium in normal adults. J. Nutr. 2001; 132: 3428-3430.

11. Bianco S.D., Peng J.R., Takanaga H. et al. Marked disturbance of calcium homeostasis in mice with targeted disruption of the Trpv6 calcium channel gene. J. Bone Miner. Res.2007; 22: 274-285.

12. Benn B.S., Ajibade D., Porta A. et al. Active intestinal calcium transport in the absence of transient receptor potential vanilloid type 6 and calbindin-D9k. Endocrinology. 2008; 149: 3196-3205.

13. Wasserman R.H., Fullmer C.S. Vitamin D and intestinal calcium transport: facts speculations and hypotheses. J. Nutr. 1995; 125: 1971S-1979S.

14. Hoenderop J.G., van Leeuwen J.P., van der Eerden B.C. et al. Renal Ca2+ wasting hyperabsorption and reduced bone thickness in mice lacking TRPV5. J. Clin. Invest. 2003; 112: 1906-1914.

15. Keller J., Schinke T. The role of the gastrointestinal tract in calcium homeostasis and bone remodeling. Osteoporos. Int. 2013; 24: 27137-2748.

16. Talmage R.V., Mobley H.T. Calcium homeostasis: Reassessement of the actions of para-thyroid hormone. Gen. Comp. Endocrinol. 2008; 156: 1-8.

17. van der Eerden B.C., Hoenderop J.G., de Vries T.J. et al. The epithelial Ca2+ channel TRPV5 is essential for proper osteoclastic bone resorption. Proc. Natl. Acad. Sci. U S A 2005; 102 (48): 17507-17512.

18. Masuyama R., Vriens J., Voets T. et al. TRPV4-mediated calcium influx regulates terminal differentiation of osteoclasts. Cell. Metab. 2008; 8 (3): 257-265.

19. Dimke H., Hoenderop J.G., Bindels R.J.M. Molecular basis of epithelial Ca2+ and Mg2+ transport: insights from the TRP channel family. J. Physiol. 2011; 589: 1535-1542.

20. Suki W.N. Calcium transport in the nephron. Am. J. Physiol. 1979; 237: F1-F6.

21. Seldin D.W. Renal handling of calcium. Nephron. 1999; 81 (Suppl 1): 2-7.

22. Ng R.C., Rouse D., Suki W.N. Calcium transport in the rabbit superficial proximal convoluted tubule. J. Clin. Invest. 1984; 74: 834-842.

23. Le Grimellec C. Micropuncture study along the proximal convoluted tubule. Electrolyte reabsorption in first convolutions. Pflugers Arch. 1975; 354: 133-150.

24. Suki W.N., Schwettmann R.S., Rector F.C., Seldin D.W. Effect of chronic mineralocorticoid administration on calcium excretion in the rat. Am. J. Physiol. 1968; 215: 71-74.

25. Hou J., Rajagopal M., Yu A.S.L. Claudins and the kidney volume 75: annual review of physiology. Annu. Rev. Physiol. 2013; 75: 479-501.

26. Muto S., Hata M., Taniguchi J. et al. Claudin-2-deficient mice are defective in the leaky and cation-selective paracellular permeability properties of renal proximal tubules. Proc. Natl. Acad. Sci. U S A. 2010; 107: 8011-8016.

27. Felsenfeld A., Rodriguez M., Levine B. New insights in regulation of calcium homeostasis. Curr. Opin. Nephrol. Hypertens. 2013; 22 (4): 371-376.

28. Hou J. New light on the role of claudins in the kidney. Organogenesis. 2012; 8 (1): 1-9.

29. Bleich V., Shan Q., Himmerkus N. Calcium regulation of tight junction permeability. Ann. N. Y. Acad. Sci. 2012; 1258: 93-99.

30. Yu A.S.L. Claudins and the kidney. J. Am. Soc. Nephrol. 2015; 26: 11-19.

31. Machen T.E., Erlij D., Wooding F.B. Permeable junctional complexes. The movement of lanthanum across rabbit gallbladder and intestine. J. Cell. Biol. 1972; 54: 302-312.

32. Марков А.Г. Белки плотных контактов клаудины: молекулярное звено парацеллюлярного транспорта. Рос. физиол. журн. им. И.М.Сеченова. 2013; 99 (2): 175-195.

33. Furuse M., Fujita K., Hiiragi T. et al. Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occluding. J. Cell. Biol. 1998; 141: 1539-1550.

34. Mineta K., Yamamoto Y., Yamazaki Y. et al. Predicted expansion of the claudin multigene family. FEBS Lett. 2011; 585: 606-612.

35. Tsukita S., Furuse M., Itoh M. Multifunctional strands in tight junctions. Nat. Rev. Mol. Cell. Biol. 2001; 2: 285-293.

36. Lal-Nag M., Morin P.J. The claudins. Genome Biol. 2009; 10 (8): 235 (Published online) URL: 10.1186/gb-2009-10-8-235.

37. Günzel D., Yu A.S.L. Function and regulation of claudins in the thick ascending limb of Henle. Pflugers Arch. 2009; 458 (1): 77-88.

38. Angelow S., Ahlstrom R., Yu A.S.L. Biology of claudins. Am. J. Physiol. Renal Physiol. 2008; 295: 867-876.

39. Terry S., Nie M., Matter K., Balda M.S. Rho signaling and tight junction functions. Physiology. 2010; 25: 16-26.

40. McCarthy K.M., Francis S.A., McCormack J.M. et al. Inducible expression of claudin-1-myc but not occluding-VSV-G results in aberrant tight junction strand formation in MDCK cells. J. Cell. Sci. 2000; 113 (Pt 19): 3387-3398.

41. Itallie C.M., Fanning A.S., Anderson J.M. eversal of charge selectivity in cation or anion-selective epithelial lines by expression of different claudins. Am. J. Physiol. Renal Physiol. 2003; 285: F1078-F1084.

42. Yu A.S., Enck A.H., Lencer W.I., Schneeberger E.E. Claudin-8 expression in Madin-Darby canine kidney cells augments the paracellular barrier to cation permeation. J. Biol. Chem. 2003; 278: 17350-17359.

43. Wen H., Watry D.D., Marcondes M.C., Fox H.S. Selective decrease in paracellular conductance of tight junctions: role of the first extracellular domain of claudin-5. Mol. Cell. Biol. 2004; 24: 8408-8417.

44. Angelow S., El-Husseini R., Kanzawa S.A., Yu A.S. Renal localization and function of the tight junction protein, claudin-19. Am. J. Physiol. Renal Physiol. 2007; 293: F166-F177.

45. Nakano Y., Kim S.H., Kim H.M. et al. A claudin-9-based ion permeability barrier is essential for hearing. PLOS Genet. 2009; 5: e1000610 (Published online) URL: 10.1371/journal.pgen.1000610.

46. Simon D.B., Lu Y., Choate K.A. et al. Paracellin-1, a renal tight junction protein, required for paracellular Mg2+ resorption. Science. 1999; 285: 103-106.

47. Kiuchi-Saishin Y., Gotoh S., Furuse M. et al. Differential expression patterns of claudins, tight junction membrane proteins, in mouse nephron segments. J. Am. Soc. Nephrol. 2002; 13: 875-886.

48. Konrad M., Schaller A., Seelow D. et al. Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular in-volvement. Am. J. Hum. Genet. 2006; 79: 949-957.

49. Ohta H., Adachi H., Takiguchi M. et al. Restricted localization of claudin-16 at the tight junction in the thick ascending limb of Henle’s loop together with claudins 3, 4 and 10 in bovine nephrons. J. Vet. Med. Sci. 2006; 68: 453-463.

50. Van Itallie C.M., Rogan S., Yu A.S. et al. Two splice variants of claudin-10 in the kidney create paracellular pores with different ion selectivities. Am. J. Physiol. Renal Physiol. 2006; 291: F1288-F1299.

51. Angelow S., Yu A.S.L. Claudins and paracellular transport: an update. Curr. Opin. Nephrol.Hypertens. 2007; 16: 459-464.

52. Muto S, Hata M., Taniguchi J. et al. Claudin-2-deficient mice are defective in the leaky and cation-selective paracellular permeability properties of renal proximal tubules. Proc. Natl. Acad. Sci. U S A. 2010; 107: 8011-8016.

53. Colegio O.R., Itallie C., Rahner C., Anderson J.M. Claudin extracellular domains determine paracellular charge selectivity and resistance but not tight junction fibril architecture. Am. J. Physiol. Cell. Physiol. 2003; 284: C1346-C1354.

54. Colegio O.R., Itallie C.M., McCrea H.J. et al. Claudins create charge-selective channels in the paracellular pathway between epithelial cells. Am. J. Physiol. Cell. Physiol. 2002; 283: C142-C147.

55. Hou J., Renigunta A., Gomes A.S. et al.Claudin-16 and claudin-19 interaction is required for their assembly into tight junction and for renal reabsorption of magnesium. Proc. Natl. Acad. Sci. U S A. 2009; 106 (36): 15350-15355.

56. Gong Y., Renigunta V., Himmerkus N. et al. Claudin-14 regulates renal Ca++ transport in response to CaSR signaling via a novel microRNA pathway. EMBO J. 2012; 31 (8): 1999-2012.

57. Ben-Yosef T., Belyantseva I.A., Saunders T.L. et al. Claudin 14 knockout mice, a model for autosomal recessive deafness DFNB29, are deaf due to cochlear hair cell degeneration. Hum. Mol. Genet. 2003; 12: 2049-2061.

58. Elkouby-Naor L., Abassi Z., Lagziel A. et al. Double gene deletion reveals lack of cooperation between claudin11 and claudin 14 tight junction proteins. Cell. Tissue Res. 2008; 333: 427-438.

59. Enck A.H., Berger U.V., Yu A.S. Claudin-2 is selectively expressed in proximal nephron in mouse kidney. Am. J. Physiol. Renal Physiol. 2001; 281: F966-F974.

60. Yu A.S., Cheng M.H., Angelow S. et al. Molecular basis for cation selectivity in claudin-2-based paracellular pores: identification of an electrostatic interaction site. J. Gen. Physiol. 2009; 133: 111-127.

61. Reilly R.F., Ellison D.H. Mammalian distal tubule: physiology, pathophysiology, and molecular anatomy. Physiol. Rev. 2000; 80: 277-313.

62. Agus Z.S., Chiu P.J., Goldberg M. Regulation of urinary calcium excretion in the rat. Am. J. Physiol. 1977; 232: F545-F549.

63. Hoenderop J.G.J., Bindels R.J.M. Epithelial Ca2+ and Mg2+ channels in health and disease. JASN. 2005; 16 (1): 15-26.

64. Романенко С.В., Костюк П.Г., Костюк Е.П. Трансмембранна кальцiєва сигналiзацiя - роль у ноцицепцiї. Журн. Акад. Мед. Наук України. 2008; 14 (1): 3-25.

65. Васильева И.О., Негуляев Ю.А., Марахова И.И., Семенова СБ. TRPV5 и TRPV6 кальциевые каналы в Т клетках человека. Цитология. 2008; 50 (11): 953-957.

66. Voets T., Prenen J., Vriens J. et al. Molecular determinants of permeation through the cation channel TRPV4. J. Biol. Chem. 2002; 277 (37): 33704-33710.

67. Hoenderop J.G., Bindels R.J. Calciotropic and magnesiotropic TRP channels. Physiology (Bethesda). 2008; 23: 32-40.

68. Hoenderop J.G., van der Kemp A.W., Hartoq A. et al. Molecular identification of the apical Ca2+ channel in 1,25-dihydroxyvitamin D3-responsive epithelia. J. Biol.Chem. 1999; 274 (13): 8375-8378.

69. Peng J.B., Chen X.Z., Berger U.V. et al. Molecular cloning and characterization of channel-like transporter mediating intestinal calcium absorption. J. Biol. Chem. 1999; 274 (32): 22739-22746.

70. Muller D., Hoenderop J.G., Merkx G.F. et al. Gene structure and chromosomal mapping of human epithelial calcium channel. Biochem. Biophys. Res. Commun. 2000; 275: 47-52.

71. Peng J.B., Brown E.M., Hediger M.A. Structural conservation of the genes encoding CaT1, CaT2 and related cation channels. Genomics. 2001; 76: 99-109.

72. Weber K., Erben R.G., Rump A., Adamski J. Gene structure and regulation of the murine epithelial calcium channels ECaC1 and 2. J. Physiol (Lond). 2001; 537: 747-761.

73. Nijenhuis T., Hoenderop J.G.J., van der Kemp A.W.C.M., Bindels R.J.M. Localization and regulation of the epithelial Ca2+ channel TRPV6 in the kidney. J. Am. Soc.Nephrol. 2003; 14 (11): 2731-2740.

74. Voets T., Janssens A., Droogmans G., Nilius B. Outer pore architecture of a Ca2+-selective TRP channel. J. Biol. Chem. 2004; 279: 15223-15230.

75. Hoenderop J.G., Nilius B., Bindels R.J. Molecular mechanisms of active Ca2+ reabsorption in the distal nephron. Annu. Rev. Physiol. 2002; 64: 529-549.

76. Lambers T.T., Mahieu F., Oancea E. et al. Calbindin D28k dynamically controls TRPV5-mediated Ca2+ transport. EMBO J. 2006; 25: 2978-2988.

77. Lee C-T., Ng H-Y., Lee Y-T. et al. The role of calbindin-D28k on renal calcium and magnesium handling during treatment with loop and thiazide diuretics. Am. J. Physiol. Renal Physiol. 2016; 310: F230-F236.

78. Bindels R.J., Hartog A., Timmermans J., Van Os C.H. Active Ca2+ transport in primary cultures of rabbit kidney CCD: Stimulation by 1,25-dihydroxyvitamin D3 and PTH. Am. J. Physiol. 1991; 261 (5 Pt 2): F799-F807.

79. Gesek F.A., Friedman P.A. Calcitonin stimulates calcium transport in distal convoluted tubule cells. Am. J. Physiol. 1993; 264 (4 Pt 2): F744-F751.

80. Friedman P.A., Coutermarsh B.A., Kennedy S.M., Gesek FA. Parathyroid hormone stimulation of calcium transport is mediated by dual signaling mechanisms involving protein ki-nase A and protein kinase C. Endocrinology. 1996; 137 (1): 13-20.

81. Peng J.B., Zhuang L., Berger U.V. et al. CaT1 expression correlates with tumor grade in prostate cancer. Biochem. Biophys. Res. Commun. 2001; 282 (3): 729-734.

82. Van Cromphaut S.J., Dewerchin M., Hoenderop J.G. et al. Duodenal calcium absorption in vitamin D receptor-knockout mice: Functional and molecular aspects. Proc. Natl. Acad. Sci. U S A. 2001; 98 (23): 13324-13329.

83. Van Cromphaut S.J., Rummens K., Stockmans I. et al. Intestinal calcium transporter genes are upregulated by estrogens and the reproductive cycle trough vitamin D receptor-independent mechanisms. J. Bone Miner. Res. 2003; 18 (10): 1725-1736.

84. Hoenderop J.G., Dardenne O., van Abel M. et al. Modulation of renal Ca2+ transport protein genes by dietary Ca2+ and 25-hydroxyvitamin D3-1α-hydroxylase knockout mice. FASEB J. 2002; 16 (11): 1398-1406.

85. Hoenderop J.G., Chon H., Gkika D. et al. Regulation of gene expression by dietary Ca2+ in kidneys of 25-hydroxyvitamin D3-1α-hydroxylase knockout mice. Kidney Int. 2004; 65 (2): 531-539.

86. Van Abel M., Hoenderop J.G., Dardenne O. et al. 1,25-dihydroxyvitamin D3-independent stimulatory effect of estrogen on the expression of ECaC1 in the kidney. J. Am. Soc. Nephrol. 2002; 13 (8): 2102-2109.

87. Boros S., Bindels R.J., Hoenderop J.G. Active Ca2+ reabsorption in the connecting tubule. Pflugers Arch. 2009; 458 (1): 99-109.

88. Hsu Y.J., Dimke H., Schoeher J.P. et al. Testosterone increases urinary calcium excretion and inhibits expression of renal calcium transport proteins. Kidney Int. 2010; 77 (7): 601-608.

89. Brown E.M., Gamba G., Riccardi D. et al. Cloning and characterization of an extracellular Ca2+-sensing receptor from bovine parathyroid. Nature. 1993; 366: 575-580.

90. Tfelt-Hansen J., Brown E.M. The calcium-sensing receptor in normal physiology and pathophysiology: a review. Crit. Rev. Clin. Lab. Sci. 2005; 42: 35-70.

91. Nemeth E.F., Steffey M.E., Hammerland L.G. et al. Calcimimetics with potent and selective activity on the parathyroid calcium receptor. Proc. Natl. Acad. Sci. U S A. 1998; 95: 4040-4045.

92. Fudge N.J., Kovacs C.S. Physiological studies in heterozygous calcium sensing receptor (CaSR) gene-ablated mice confirm that the CaSR regulates calcitonin release in vivo. BMC Physiol. 2004; 4: 5.

93. Brauner-Osborne H., Wellendorph P., Jensen A.A. Structure, pharmacology and therapeutic prospects of family C G-protein coupled receptors. Curr. Drug Targets. 2007; 8: 169-184.

94. Aida K., Koishi S., Tawata M., Onaya T. Molecular cloning of a putative Ca(2+)-sensing receptor cDNA from human kidney. Biochem. Biophys. Res. Commun. 1995; 214 (2): 524-529.

95. Janicic N., Soliman E., Pausova Z. et al. Mapping of the calcium-sensing receptor gene (CASR) to human chromosome 3q13.3-21 by fluorescence in situ hybridization, and localization to rat chromosome 11 and mouse chromosome 16. Mamm. Genome. 1995; 6 (11): 798-801.

96. Garrett J.E., Capuano I.V., Hammerland L.G. et al. Molecular cloning and functional expression of human parathyroid calcium receptor cDNAs. J. Biol. Chem. 1995; 270 (21): 12919-12925.

97. Silve C., Petrel C., Leroy C. et al. Delineating a Ca2+ binding pocket within the venus flytrap module of the human calcium-sensing receptor J. Biol. Chem. 2005; 280: 37917-37923.

98. Huang C., Miller R.T. The calcium-sensing receptor and its interacting proteins. J. Cell. Mol. Med. 2007; 11: 923-934.

99. Conigrave A.D., Mun H.C., Brennan S.C. Physiological significance of l-amino acid sensing by extracellular Ca2+-sensing receptors. Biochem. Soc. Trans. 2007; 35: 1195-1198.

100. Hu J., Spiegel A.M. Naturally occurring mutations in the extracellular Ca2+-sensing receptor: implications for its structure and function. Trends Endocrinol. Metab. 2003; 14: 282-288.

101. Gowen M., Stroup G.B., Dodds R.A. et al. Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion and bone formation in osteopenic rats. J. Clin. Invest. 2000; 105: 1595-1604.

102. Brown E.M. Clinical lessons from the calcium-sensing receptor. Nat. Clin. Pract. Endocrinol. Metab. 2007; 3: 122-133.

103. Mithal A., Kifor O., Kifor I. et al. The reduced responsiveness of cultured bovine parathyroid cells to extracellular Ca2+ is associated with marked reduction in the expression of extracellular Ca(2+)-sensing receptor messenger ribonucleic acid and protein. Endocrinology. 1995; 136 (7): 3087-3092.

104. Garfia B., Canadillas S., Canalejo A. et al. Regulation of parathyroid vitamin D receptor expression by extracellular calcium. J. Am. Soc. Nephrol. 2002; 13: 2945-2952.

105. Riccardi D., Hall A.E., Chattopadhyay N. et al. Localization of extracellular Ca2+/polyvalent cation-sensing protein in rat kidney. Am. J. Physiol. Renal Physiol. 1998; 274: F611-F622.

106. Riccardi D., Lee W.C., Lee K. et al. Localization of the extracellular Ca2+-sensing receptor and PTH/PTHrP receptor in rat kidney. Am. J. Physiol. Renal Fluid Electrolyte Physiol. 1996; 271: F951-F956.

107. Topala C.N., Schoeber J.P., Searchfield L.E. Activation of the Ca2+-sensing receptor stimulates the activity of the epithelial Ca2+ channel TRPV5. Cell. Calcium 2009; 45: 331-339.

108. Renkema K.Y., Velic A., Dijkman H.B. et al. The calcium-sensing receptor promotes urinary acidification to prevent nephrolithiasis. J. Am. Soc. Nephrol. 2009; 20: 1705-1713.

109. Beierwaltes W.H. The role of calcium in the regulation of renin secretion. Am. J. Physiol. Renal Physiol. 2010; 298: F1-F11.

110. Egbuna O., Quinn S., Kantham L. et al. The full-length calcium-sensing receptor dampens the calcemic response to 1 alpha, 25(OH)2 vitamin D3 in vivo independent of parathyroid hormone. Am. J. Physiol. Renal Physiol. 2009; 297: F720-F728.

111. Riccardi D., Traebert M., Ward D.T. et al. Dietary phosphate and parathyroid hormone alter the expression of calcium-sensing receptor (CaR) and the Na+-dependent Pi transporter (NaPi-2) in the rat proximal tubule. Pflugers Arch. 2000; 441: 379-387.

112. Canaff L., Hendy G.N. Human calcium-sensing receptor gene. Vitamin D response elements in promoters P1 and P2 confer transcriptional responsiveness to 1,25-dihydrovitamin D. J. Biol. Chem. 2002; 277: 30337-30350.

113. Wang W.H., Lu M., Hebert S.C. Cytochrome P-450 metabolites mediate extracellular Ca2+-induced inhibition of apical K+ channels in the TAL. Am. J. Physiol. Cell. Physiol. 1996; 271: C103-C111.

114. Sands J.M., Naruse M., Baum M. et al. Apical extracellular calcium/polyvalent cation-sensing receptor regulates vasopressinelicited water permeability in rat kidney inner medullary collecting duct. J. Clin. Invest. 1997; 99: 1399-1405.

115. Valenti G., Procino G., Tamma G. et al. Minireview: aquaporin 2 trafficking. Endocrinology. 2005; 146: 5063-5070.

116. Pearce S.H., Williamson C., Kifor O. et al. A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor. N. Engl. J. Med. 1996; 335: 1115-1122.

117. Alfadda T.I., Saleh A.M.A., Houiller P., Geibel J.P. Calcium-sensing receptor 20 years later. Am. J. Physiol. Cell. Physiol. 2014; 307: C221-C231.

118. Kantham L., Quinn S.J., Egbuna O.I. et al. The calcium-sensing receptor (CaSR) defends against hypercalcemia independently of its regulation of parathyroid hormone secretion. Am. J. Physiol. Endocrinol. Metab. 2009; 94: 4749-4756.

119. Geibel J.P., Hebert S.C. The function and roles of the extracellular Ca2+-sensing receptor along the gastrointestinal tract. Annu. Rev. Physiol. 2009; 71: 205-217.

120. Quarles L.D., Hartle J.E 2., Siddhanti S.R. et al. A distinct cation-sensing mechanism in MC3T3-E1 osteoblasts functionally related to the calcium receptor. J. Bone Miner. Res. 1997; 12 (3): 393-402.

121. Kameda T., Mano H., Yamada Y. et al. Calcium-sensing receptor in mature osteoclasts, which are bone-resorbing cells. Biochem. Biophys. Res. Commun. 1998; 245 (2): 419-422.

122. Yamaguchi T., Kifor O., Chattopadhyay N., Brown E.M. Expression of extracellular calcium (Ca2+o)-sensing receptor in the clonal osteoblast-like cell lines, UMR-106 and SAOS-2. Biochem. Biophys. Res. Commun. 1998; 243 (3): 753-757.

123. Dvorak M.M., Siddiqua A., Ward D.T. et al. Physiological changes in extracellular calcium concentration directly control osteoblast function in the absence of calciotropic hormones. Proc. Natl. Acad. Sci. U S A. 2004; 101: 5140-5145.

124. Chang W., Tu C., Chen T.H. et al. The extracellular calcium-sensing receptor (CaSR) is a critical modulator of skeletal development. Sci. Signal. 2008; 1 (35): 1-13.

125. Kovacs C.S., Ho-Pao C.L., Hunzelman J.L. et al. Regulation of murine fetal-placental calcium metabolism by the calcium-sensing receptor. J. Clin. Invest. 1998; 101: 2812-2820.

126. VanHouten J., Dann P., McGeoch G. et al. The calcium-sensing receptor regulates mammary gland parathyroid hormone-related protein production and calcium transport. J. Clin. Invest. 2004; 113: 598-608.

127. McNeil S.E., Hobson S.A., Nipper V., Rodland K.D. Functional calcium-sensing receptors in rat fibroblasts are required for activation of SRC kinase and mitogen-activated protein kinase in response to extracellular calcium. J. Biol. Chem. 1998; 273 (2): 1114-1120.

128. Bikle D.D., Ratnam A., Mauro T. et al. Changes in calcium responsiveness and handling during keratinocyte differentiation. Potential role of the calcium receptor. J. Clin. Invest. 1996; 97 (4): 1085-1093.

129. Chakrabarty S., Wang H., Canaff L. et al. Calcium sensing receptor in human colon carcinoma: interaction with Ca(2+) and 1,25-dihydroxyvitamin D(3). Cancer Res. 2005; 65 (2): 493-498.

130. Chattopadhyay N., Ye C., Singh D.P. et al. Expression of extracellular calcium-sensing receptor by human lens epithelial cells. Biochem. Biophys. Res. Commun. 1997; 233 (3): 801-805.

131. Lin K.I., Chattopadhyay N., Bai M. et al. Elevated extracellular calcium can prevent apoptosis via the calcium-sensing receptor. Biochem. Biophys. Res. Commun. 1998; 249 (2): 325-331.

132. Van Den Hurk M.J., Jenks B.G., Roubos E.W., Scheenen W.J. The extracellular calcium-sensing receptor increases the number of calcium steps and action currents in pituitary melanotrope cells. Neurosci. Lett. 2005; 377 (2): 125-129.

133. Kato M., Dai R., Imamure M. et al. Calcium-evoked insulin release from insulinoma cells is mediated via calcium-sensing receptor. Surgery. 1997; 122 (6): 1203-1211.

134. Ray J.M., Squires P.E., Curtis S.B. et al. Expression of calcium sensing receptor on human antral gastrin cells in culture. J. Clin. Invest. 1997; 99 (10): 2328-2333.

135. Canaff L., Petit J.L., Kisiel M. et al. Extracellular calcium-sensing receptor is expressed in rat hepatocytes coupling to intracellular calcium mobilization and stimulation of bile flow. J. Biol. Chem. 2001; 276 (6): 4070-4079.

136. D’Souza-Li L. The calcium-sensing receptor and related diseases. Arq. Bras. Endocrinol. Metab. 2006; 50 (4): 628-639.

137. Jahnen-Dechent W., Ketteler M. Magnesium basics. Clin. Kidney J. 2012; 5 (Suppl 1): i3-i14.

138. de Baaij J.H.F., Hoenderop J.G.J., Bindels R.J. Magnesium in man: implications for health and disease. Physiol. Rev. 2015; 95. 1-46.

139. Спасов А.А. Магний в медицинской практике. Волгоград, Отрок, 2000; 272 c.

140. Fine K.D., Santa Ana C.A., Porter J.L., Fordtran J.S. Intestinal absorption of magnesium from food and supplements. J. Clin. Invest. 1991; 88: 396-402.

141. Kerstan D., Quamme G. Physiology and pathophysiology of intestinal absorption of magnesium. In: Massry SG, Morii H, Nishizawa Y, eds. Calcium in internal medicine. Springer-Verlag London, 2002; 171-183.

142. Konrad M., Weber S. Recent advances in molecular genetics of hereditary magnesium-losing disorders. J. Am. Soc. Nephrol. 2003; 14 (1): 249-260.

143. Schlingmann K.P., Weber S., Peters M. et al. Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nat. Genet. 2002; 31 (2): 166-170.

144. Walder R.Y., Landau D., Meyer P. et al. Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia. Nat. Genet. 2002; 31 (2): 171-174.

145. Ryazanova L.V., Rondon L.J., Zierler S. et al. TRPM7 is essential for Mg(2+) homeostasis in mammals. Nat. Commun. 2010; 1: 109.

146. Boskey A.L., Rimnac C.M., Bansal M. et al. Effect of short-term hypomagnesemia on the chemical and mechanical properties of rat bone. J. Orthop. Res. 1992; 10 (6): 774-783.

147. Kenney M.A., McCoy H., Williams L. Effects of magnesium deficiency on strength, mass, and composition of rat femur. Calcif. Tissue Int. 1994; 54 (1): 44-49.

148. Liu C., Yeh J., Alola J. Magnesium directly stimulates osteoblast proliferation. J. Bone Miner. Res. 1988; 3: S104.

149. Rude R.K., Gruber H.E., Norton H.J. et al. Bone loss induced by dietary magnesium reduction to 10% of the nutrient requirement in rats is associated with increased release of sub-stance P and tumor necrosis factor-alpha. J. Nutr. 2004; 134: 79-85.

150. Quamme G.A. Laboratory evaluation of magnesium status. Renal function and free intracellular magnesium concentration. Clin. Lab. Med. 1993; 13: 209-223.

151. Kelepouris E., Agus Z.S. Hypomagnesemia: renal magnesium handling. Semin. Nephrol. 1998; 18: 58-73.

152. Quamme G.A., de Rouffignac C. Epithelial magnesium transport and regulation by the kidney. Front. Biosci. 2000; 5: D694-D711.

153. Leliévre-Pegorier M., Merlet-Bénichou C., Roinel N., de Rouffignac C. Developmental pattern of water and electrolyte transport in the superficial nephron. Am. J. Physiol. 1983; 244: F15-F21.

154. Wong N.L., Whiting S.J., Mizgala C.L., Quamme G.A. Electrolyte handling by the superficial nephron of the rabbit. Am. J. Physiol. 1986; 250: F590-F595.

155. Satoh J., Romero M.F. Ma2+ transport in the kidney. BioMetals. 2002; 15: 285-295.

156. Suki W.N., Rouse D., Ng R.C., Kokko J.P. Calcium transport in the thick ascending limb of Henle. Heterogeneity of function in the medullary and cortical segments. J. Clin. Invest. 1980; 66: 1004-1009.

157. Quamme G.A. Effect of furosemide on calcium and magnesium transport in the rat nephron. Am. J. Physiol. 1981; 241: F340-F347.

158. Quamme G.A. Renal magnesium handling: New insights in understanding old problems. Kidney Int. 1997; 52: 1180-1195.

159. Konrad M., Schaller A., Seelow D. et al. Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement. Am. J. Hum. Genet. 2006; 79: 949-957.

160. Efrati E., Arsentiev-Rosenfeld J., Zelikovic I. The human paracellin-1gene (hPCLN-1): renal epithelial cell-specific expression and regulation. Am. J. Physiol. Renal. Physiol. 2005; 288 (2): F272-F283.

161. Breiderhoff T., Himmerkus N., Stuiver M. et al. Deletion of claudin-10 (Cldn 10) in the thick ascending limb impairs paracellular sodium permeability and leads to hyper-magnesemia and nephrocalcinosis. Proc. Natl. Acad. Sci. U S A. 2012; 109: 14241-14246.

162. Wright F.S. Increasing magnitude of electrical potential along the renal distal tubule. Am. J. Physiol. 1971; 220: 624-638.

163. Malnic G., Giebisch G. Some electrical properties of distal tubular epithelium in the rat. Am. J. Physiol. 1972; 223: 797-808.

164. Quamme G.A., Dirks J.H. Intraluminal and contraluminal magnesium on magnesium and calcium transfer in the rat nephron. Am. J. Physiol. 1980; 238: F187-F198.

165. Dai L.J., Ritchie G., Kerstan D. et al. Magnesium transport in the renal distal convoluted tubule. Physiol. Rev. 2001; 81 (1): 51-84.

166. Grubbs R.D. Inracellular magnesium and magnesium buffering. BioMetals. 2002; 15: 251-259.

167. Voets T., Nilius B., Hoefs S. et al. TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption. J. Biol. Chem. 2004; 279: 19-25.

168. Schlingmann K.P., Weber S., Peters M. et al. Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nat. Genet. 2002; 31 (2): 166-170.

169. Walder R.Y., Landau D., Meyer P. et al. Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia. Nat. Genet. 2002; 31 (2): 171-174.

170. Runnels L.W., Yue L., Clapham D.E. TRP-PLIK, a bifunctional protein with kinase and ion channel activities. Science 2001; 291 (5506): 1043-1047.

171. Chubanov V., Gudermann T., Schlingmann K.P. Essential role for TRPM6 in epithelial magnesium transport and body magnesium homeostasis. Pflugers Arch. 2005; 451 (1): 228-234.

172. Schlingmann K.P., Waldegger S., Konrad M. et al. TRPM6 and TRPM7 - Gatekeepers of human magnesium metabolism. Biochim. Biophys. Acta. 2007; 1772 (8): 813-821.

173. Groenestege W.M., Thébault S., van der Wijst J. et al. Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia. J. Clin. Invest. 2007; 117 (8): 2260-2267.

174. Glaudemans B., Knoers N.V., Hoenderop J.G., Bindels R.J. New molecular players facilitating Mg(2+) reabsorption in the distal convoluted tubules. Kidney Int. 2010; 77 (1): 17-22.

175. Pham P-C.T., Pham P-A.T., Pham S.V. et al. Hypomagnesemia: a clinical perspective. Int. J. Nephrol. Renovasc. Dis. 2014; 7: 219-230.

176. Glaudemans B., van der Wijst J., Scola R.H. et al. A missense mutation in the Kv1.1 voltage-gated potassium channel-encoding gene KCNA1 is linked to human autosomal dominant hypomagnesemia. J. Clin. Invest. 2009; 119 (4): 936-942.

177. Romani A.M.P. Cellular magnesium homeostasis. Arch. Biochem. Biophys. 2011; 512 (1): 1-23.

178. Günther T., Vormann J., Förster R. Regulation of intracellular magnesium by Mg2+ efflux. Biochem. Biophys. Res. Commun. 1984; 119 (1): 124-131.

179. Günther T., Vormann J. Mg2+ efflux is accomplished by an amiloride-sensitive Na+/Mg2+ antiport. Biochem. Biophys. Res. Commun. 1985; 130 (2): 540-545.

180. Féray J.C., Garay R. A Na+-stimulated Mg2+-transport system in human red blood cells. Biochem. Biophys. Acta. 1986; 856 (1): 76-84.

181. Lüdi H., Schatzmann H.J. Some properties of a system for sodium-dependent outward movement of magnesium from metabolizing human red blood cells. J.Physiol. 1987; 390: 367-382.

182. Flatman P.W., Smith L.M. Magnesium transport in ferret red cells. J. Physiol. 1990; 431: 11-25.

183. Xu W., Willis J.S. Sodium transport through the amiloride-sensitive Na-Mg pathway of hamster red cells. J. Membr. Biol. 1994; 141 (3): 277-287.

184. Romani A., Mafella C., Scarpa A. Regulation of magnesium uptake and release in the heart and in isolated ventricular myocytes. Circ. Res. 1993; 72 (6): 1139-1148.

185. Fagan T.E., Romani A. Activation of Na(+)- and Ca(2+)-dependent Mg(2+) extrusion by alpha(1)- and beta-adrenergic agonists in rat liver cells. Am. J. Physiol. Gastrointest. Liver Physiol. 2000; 279 (5): G943-G950.

186. Günther T., Vormann J. Activation of Na+/Mg2+ antiport in thymocytes by cAMP. FEBS Lett. 1992; 297 (1-2): 132-134.

187. Wolf F.I., Di Francesco A., Covacci V. et al. Regulation of intracellular magnesium in ascites cells: involvement of different regulatory pathways. Arch. Biochem. Biophys. 1996; 331 (2): 194-200.

188. Fagan T.E., Romani A. alpha(1)-Adrenoceptor-induced Mg2+ extrusion from rat hepatocytes occurs via Na+-dependent transport mechanism. Am. J. Physiol. Gastrointest. Liver Physiol. 2001; 280 (6): G1145-G1156.

189. Cefaratti C., Romani A.M. Functional characterization of two distinct Mg(2+) extrusion mechanisms in cardiac sarcolemmal vesicles. Mol. Cell. Biochem. 2007; 303 (1-2): 63-72.

190. Cefaratti C., Ruse C. Protein kinase A dependent phosphorylation activates Mg2+ efflux in the basolateral region of the liver. Mol. Cell. Biochim. 2007; 297 (1-2): 209-214.

191. Günther T. Mechanisms and regulation of Mg2+ efflux and Mg2+ influx. Miner, Electrolyte Metab. 1993; 19 (4-5): 259-265.

192. Ebel H., Hollstein M., Gunther T. Role on the choline exchanger in Na(+)-independent Mg(2+) efflux from rat erythrocytes. Biochim. Biophys. Acta. 2002; 1559 (2): 135-144.

193. Stuiver M., Lainez S., Will C. et al. CNNM2, encoding a basolateral protein required for renal Mg2+ handling, is mutated in dominant hypomagnesemia. Am. J. Hum. Genet. 2011; 88 (3): 333-343.

194. de Baaij J.H., Stuiver M., Meij I.C. et al. Membrane topology and intracellular processing of cyclin M2 (CNNM2). J. Biol. Chem. 2012; 287 (17): 13644-13655.

195. Wang C.Y., Shi J.D., Yang P. et al. Molecular cloning and characterization of a novel gene family of four ancient conserved domain proteins (ACDP). Gene. 2003; 306: 37-44.

196. Wang C.Y., Yang P., Shi J.D. et al. Molecular cloning and characterization of the mouse Acdp gene family. BMC Genomics. 2004; 5: 7.

197. Goytain A., Quamme G.A. Functional characterization of ACDP2 (ancient conserved domain protein, a divalent metal transporter. Physiol. Genomics. 2005; 22: 382-389.

198. Quamme G.A. Control of magnesium transport in the thick ascending limb. Am. J. Physiol. 1989; 256: F197-F210.

199. Dai L.J., Quamme G.A. Intracellular Mg2+ and magnesium depletion in isolated renal thick ascending limb cells. J. Clin. Invest. 1991; 88: 1255-1264.

200. Dai L.J., Bapty B.W., Ritchie G., Quamme G.A. PGE2 stimulates Mg2+ uptake in mouse distal convoluted tubule cells. Am. J. Physiol. Renal Physiol. 1998. 275: F833-F839.

201. Dai L.J., Bapty B.W., Ritchie G. et al.Insulin stimulates Mg2+ uptake in mouse distal convoluted tubule cells. Am. J. Physiol. Renal Physiol. 1999. 277: F907-F913.

202. Yang T., Hassan S., Huang Y.G. et al. Expression of PTHrP, PTH/PTHrP receptor and Ca2+ sensing receptor along the rat nephron. Am. J. Physiol. Renal Physiol. 1997; 272: F751-F758.

203. Bapty B.W., Dai L.J, Ritchie G. et al. Extracellular Mg2+ and Ca2+ sensing in mouse distal convoluted tubule cells. Kidney Int. 1998; 53: 583-592.

204. Braüner-Osborne H., Jensen A.A., Sheppard P.O. et al. The agonist-binding domain of the calcium-sensing receptor is located at the amino-terminal domain. J. Biol. Chem. 1999; 274 (26): 18382-18386.