medigraphic.com
Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán

2014, Número 6

<< Anterior

Rev Invest Clin 2014; 66 (6)


Aspectos estructurales, funcionales y patológicos del cotransportador de NaCl sensible a tiazidas

Moreno E, Pacheco-Alvarez D, Ríos AE

Idioma: Español
Referencias bibliográficas: 61
Paginas: 559-567
Archivo PDF: 219.22 Kb.


RESUMEN

El cotransportador de Na-Cl sensible a tiazidas (NCC o CST) es la principal vía de reabsorción de sal en el túbulo distal de la nefrona y es el sitio de acción de los diuréticos de tipo tiazida que, por su utilidad en el manejo de la hipertensión arterial, se encuentran dentro de los medicamentos más recetados en el mundo. El NCC es una proteína de suma importancia para la fisiología renal, ya que permite mantener la homeostasis de sal y agua en el organismo. Cuando suceden mutaciones inactivantes en el gen que codifica para este cotransportador se produce una enfermedad conocida como síndrome de Gitelman, el cual es un trastorno autosómico recesivo caracterizado clínicamente por hipotensión arterial, alcalosis metabólica, hipocalemia e hipocalciuria, lo que resalta la importancia de este gen en la regulación de la presión arterial y el equilibrio hidroelectrolítico. En este trabajo hacemos una breve revisión de los conocimientos que se tienen acerca de este cotransportador, con especial énfasis en la biología molecular, propiedades fisiológicas y aspectos patológicos del NCC.


REFERENCIAS (EN ESTE ARTÍCULO)

  1. Gamba G. Molecular Physiology and Pathophysiology of the electroneutral cation-chloride cotransporters. Physiol Rev 2005; 85 (2):423-93.

  2. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, et al. Evidence-Based Guideline for the Management of High Blood Pressure in AdultsReport From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311(5): 507-20.

  3. Novello FC, Sprague JM. Benzothiadiazine dioxides as novel diuretics. J Am Chem Soc 1957; 79(8): 2028-9.

  4. ENSANUT. Disponible en: http://ensanut insp.mx/

  5. Gitelman HJ, Graham JB, Welt LG. A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Physicians 1996; 79: 221-35.

  6. Simon DB, Lifton RP. The molecular basis of inherited hypokalemic alkalosis:Bartter’s ans Gitelman’s syndromes. Am J Physiol. (Renal Fluid Electrolyte Physiol) 1996; 271(5; pt.2): F961-F966.

  7. Gamba G, Saltzberg SN, Lombardi M, Miyanoshita A, Lytton J, Hediger MA, Brenner BM, et al. Primary structure and functional expression of a cDNA encoding the thiazide-sensitive, electroneutral sodium-chloride cotransporter. Proc Natl Acad Sci USA 1993; 90(7): 2749-53.

  8. Velazquez H, Naray-Fejes-Toth A, Silva T, Andujar E, Reilly RF, Desir GV, Ellison DH. Rabbit distal convoluted tubule coexpresses NaCl cotransporter and 11 beta-hydroxysteroid dehydrogenase II mRNA. Kidney Int 1998; 54(2): 464-72.

  9. Gamba G, Miyanoshita A, Lombardi M, Lytton J, Lee WS, Hediger MA, Hebert SC. Molecular cloning, primary structure and characterization of two members of the mammalian electroneutral sodium-(potassium)-chloride cotransporter family expressed in kidney. J Biol Chem 1994; 269(26): 17713-22.

  10. Kunchaparty S, Palcso M, Berkman J, Velázquez H, Desir GV, Bernstein P, Reilly RF and Ellison DH. Defective processing and expression of thiazide-sensitive Na-Cl cotransporter as a cause of Gitelman’s syndrome. Am J Physiol 1999; 277 (4; pt.2): F643-F649.

  11. Simon DB, Nelson-Williams C, Johnson-Bia M, Ellison D, Karet FE, Morey-Molina A, Vaara I, et al. Gitelman’s variant of Bartter’s syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nature Genetics 1996; 12(1): 24-30.

  12. Mastroianni N, Fusco MD, Zollo M, Arrigo G, Zuffardi O. Molecular cloning, expression pattern, and chromosomal localization of the human Na-Cl thiazide-sensitive cotransporter (SLC12A3). Genomics 1996; 35(3): 486-93.

  13. Cutler C, Cramb G. Differential expression of absorptive cation- chloride-cotransporters in the intestinal and renal tissues of the European eel (Anguilla-anguilla). Comparative Biochemistry and Physiology B Biochem Mol Biol 2008; 149(1): 63-73.

  14. Taniyama Y, Sato K, Sugawara A, Uruno A, Ikeda Y, Kudo M, Ito S,et al. Renal tubule-specific transcription and chromosomal localization of rat thiazide-sensitive Na-Cl cotransporter gene. J Biol Chem 2001; 276(28): 26260-8.

  15. Pathak BG, Shaughnessy JD Jr., Meneton P, Greeb J, Shull GE, Jenkins NA, Copeland NG. Mouse chromosomal location of three epithelial sodium channel subunit genes and an apical sodium chloride cotransporter gene. Genomics 1996; 33(1): 124-7.

  16. Hoover RS, Poch E, Monroy A, Vázquez N, Nishio T, Gamba G, Hebert SC. N-Glycosylation at two sites critically alters thiazide binding and activity of the rat thiazide-sensitive Na(+):Cl(-) cotransporter. J Am Soc Nephrol 2003; 14(2): 271- 82.

  17. Bachmann S, Velázquez H, Obermuller N, Reily RF, Moser D, Ellison D. Expression of the thiazide-sensitive Na-Cl cotransporter by rabbit distal convoluted tubule cells. J Clin Invest 1995; 96(5): 2510-14.

  18. Plotkin MD, Kaplan MR, Verlander JM, Lee WS, Brown D, Poch E, Gullans SR, et al. Localization of the thiazide sensitive Na-Cl cotransporter, rTSC1, in the rat kidney. Kidney Int 1996; 50(1): 174-83.

  19. Bazzini C, Vezzoli V, Sironi C, Dossena S, Ravasio A, Debiasi S, Garavaglia M,et al. Thiazide-sensitive NaCl cotransporter in the intestine: possible role of HCTZ in the intestinal Ca2+ uptake. J Biol Chem 2005; 280(20): 19902-10.

  20. Dvorak MM, DeJoussineau C, Carter DH, Pisitkun T, Knepper MA, Gamba G, Kemp PJ, et al. Thiazide diuretics directly induce osteoblast differentiation and mineralized nodule formation by interacting with a sodium chloride co-transporter in bone. J Am Soc Nephrol 2007; 18(9): 2509-16.

  21. Deng L, Chen G. Cyclothiazide potently inhibits gamma-aminobutyric acid type A receptors in addition to enhancing glutamate responses. Proc Natl Acad Sci USA 2003; 100(22): 13025-9.

  22. Clader JA, Schacheter M, Sever PS. Direct vascular actions of hydrochlorothaizide and indapamide in isolated small vessels. Eur J Pharmacol 1992; 220(1): 19-26.

  23. Bernstein PL, Zawalach W, Bartiss A, Reilly R, Palcso M, Ellison DH. The thiazide-sensitive Na-Cl cotransporter is expressed in rat endocrine pancreas. Journal Amer Soc Nephrology 1995; 6(3): 732.

  24. Abuladze N, Yanagawa N, Lee I, Jo OD, Newman D, Hwang J, Uyemura K, et al. Peripheral blood mononuclear cells express mutated NCCT mRNA in Gitelman’s syndrome: evidence for abnormal thiazide-sensitive NaCl cotransport. J Am Soc Nephrol 1998; 9(5): 819-26.

  25. Cremaschi D, Porta C, Botta G, Bazzini C, Baroni MD, Garavaglia M. Apical Na(+)-Cl(-) symport in rabbit gallbladder epithelium: a thiazide-sensitive cotransporter (TSC). J Membr Biol 2000; 176(1): 53-65.

  26. Drewnowska K, Baumgarten CM. Regulation of cellular volume in rabbit ventricular myocytes: bumetanide, chlorthiazide, and ouabain. Am J Physiol Cell Physiol 1991; 260(1; pt.1): C122-C131.

  27. De Jong JC, Willems PH, Mooren FJ, van den Heuvel LP, Knoers NV, Bindels RJ. The structural unit of the thiazide-sensitive NaCl cotransporter is a homodimer. J Biol Chem 2003; 278(27): 24302-7.

  28. Monroy A, Plata C, Hebert SC, Gamba G. Characterization of the thiazide-sensitive Na(+)-Cl(-) cotransporter: a new model for ions and diuretics interaction. Am J Physiol Renal Physiol 2000; 279(1): F161-F169.

  29. Vazquez N, Monroy A, Dorantes E, Munoz-Clares RA, Gamba G. Functional differences between flounder and rat thiazidesensitive Na- Cl cotransporter. Am J Physiol Renal Physiol 2002; 282(4): F599-F607.

  30. Moreno E, San Cristobal P, Rivera M, Vazquez N, Bobadilla NA, Gamba G. Affinity defining domains in the Na-Cl cotransporter: different location for Cl- and thiazide binding. J Biol Chem 2006; 281(39): 17266-75.

  31. Tran JM, Farrell MA, Fanestil DD. Effect of ions on binding of the thiazide-type diuretic metolazone to kidney membrane. Am J Physiol Renal Fluid Electrolyte Physiol 1990; 258(4; pt.2): F908-F915.

  32. Moreno E, Tovar-Palacio C, De Los HP, Guzman B, Bobadilla NA, Vazquez N, Riccardi D, et al. A single nucleotide polymorphism alters the activity of the renal Na:Cl cotransporter and reveals a role for transmembrane segment 4 in chloride and thiazide affinity. J Biol Chem 2004; 279(16): 16553-60.

  33. Vormfelde SV, Sehrt D, Toliat MR, Schirmer M, Meineke I, Tzvetkov M, NurnbergP, et al. Genetic variation in the renal sodium transporters NKCC2, NCC, and ENaC in relation to the effects of loop diuretic drugs. Clin Pharmacol Ther 2007; 82(3): 300-9.

  34. Castañeda-Bueno M, Vázquez N, Bustos J, Hernández D, Rodríguez- Lobato E, Pacheco-Alvarez D, Cariño-Cortés R, et al. A single residue in transmembrane domain 11 defines the different affinity for thiazides between the mammalian and flounder NaCl transporters. Am J Physiol Renal Physiol 2010; 299(5): F1111-F1119.

  35. Pacheco-Alvarez D, San Cristobal P, Meade P, Moreno E, Vazquez N, Munoz E, Diaz A, et al. The Na-Cl cotransporter is activated and phosphorylated at the amino terminal domain upon intracellular chloride depletion. J Biol Chem 2006; 281(39): 28755-63.

  36. Garzon-Muvdi T, Pacheco-Alvarez D, Gagnon KB, Vazquez N, Ponce-Coria J, Moreno E, Delpire E, et al. WNK4 Kinase is a Negative Regulator of K+-Cl- Cotransporters. Am J Physiol Renal Physiol 2007; 292(4): F1197-F1207.

  37. Plata C, Escamilla J, Carrillo E, Galindo JM, Gamba G, Garcia MC, Sanchez JA. AKAP79 increases the functional expression of skeletal muscle Ca2+ channels in Xenopus oocytes. Biochem Biophys Res Commun 2004; 316(1): 189-94.

  38. Meade P, Hoover RS, Plata C, Vazquez N, Bobadilla NA, Gamba G, Hebert SC. cAMP-dependent activation of the renalspecific Na+-K+-2Cl- cotransporter is mediated by regulation of cotransporter trafficking. Am J Physiol Renal Physiol 2003; 284(6): F1145-F1154.

  39. Tovar-Palacio C, Bobadilla NA, Cortes P, Plata C, De Los HP, Vazquez N, Gamba G. Ion and Diuretic Specificity of Chimeric Proteins Between Apical Na+:K+:2Cl- and Na+:Cl- Cotransporters. Am J Physiol Renal Physiol 2004; 287(3): F570-F577.

  40. Gordon RD. Syndrome of hypertension and hyperkalemia with normal glomerular filtration rate. Hypertension 1986; 8(2): 93-102.

  41. Bartter FC, Pronove P, Gill JR, MacCardle RC. Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome. JASN 1998; 9(3): 516-28.

  42. Kurtz I. Molecular pathogenesis of Bartter’s and Gitelman’s syndromes. Kidney Int 1998; 54(4): 1396-410.

  43. Bettinelli A, Bianchetti MG, Girardin E, Caringella A, Cecconi M, Appiani AC, et al. Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis: Bartter and Gitelman syndromes. J Pediatr 1992; 120(1): 38-43.

  44. Gladziwa U, Schwarz R, Gitter AH, Bijman J, Seyberth H, Beck F, et al. Chronic hypokalaemia of adults: Gitelman’s syndrome is frequent but classical Bartte’s syndrome is rare. Nephrol Dial Transplant 1995; 10(9): 1607-13.

  45. Ji W, Foo JN, O’Roak BJ, Zhao H, Larson MG, Simon DB, et al. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet 2008; 40(5): 592-9.

  46. Acuña R, Martínez-de-la-Maza L, Ponce-Coria J, Vázquez N, Ortal-Vite P, Pacheco-Álvarez D, Bobadilla NA, et al. Rare mutations in SLC12A1 and SLC12A3 protect against hypertension by reducing the activity of renal salt cotransporters. J Hypertens 2011; 29(3): 475-83.

  47. Gamba G. Physiology and Pathophysiology of the NaCl Co-Transporters in the Kidney. In: Alpern RJ, Caplan MJ, Moe OW (eds.). Seldin and Giebisch’s The Kidney Physiology Pathophysiology. 5th ed. USA, Academic Press, 2012; pp. 1047-80.

  48. Berry MR, Robinson C, Karet Frankl FE. Unexpected clinical sequelae of Gitelman syndrome: hypertension in adulthood is common and females have higher potassium requirements. Nephrol Dial Transplant. Oxford University 2013; 28(6): 1533-42.

  49. Ea H-K, Blanchard A, Dougados M, Roux C. Chondrocalcinosis secondary to hypomagnesemia in Gitelman’s syndrome. J Rheumatol 2005; 32(9): 1840-2.

  50. Halperin ML. Fluid, Electrolyte and Acid-Base Physiology. 4th ed. USA, Saunders, 616 pages. 2010.

  51. Nijenhuis T, Vallon V, van der Kemp AWCM, Loffing J, Hoenderop JGJ, Bindels RJM. Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide- induced hypocalciuria and hypomagnesemia. J Clin Invest. American Society for Clinical Investigation 2005; 115(6): 1651-8.

  52. Friedman PA. Codependence of renal calcium and sodium transport. Annu Rev Physiol 1998; 60(1): 179-97.

  53. Dimke H, Monnens L, Hoenderop JGJ, Bindels RJM. Evaluation of Hypomagnesemia: Lessons From Disorders of Tubular Transport. Elsevier Inc 2013; 62(2): 377-83.

  54. Demoulin N, Aydin S, Cosyns J-P, Dahan K, Cornet G, Auberger I, et al. Gitelman syndrome and glomerular proteinuria: a link between loss of sodium-chloride cotransporter and podocyte dysfunction. Nephrol Dial Transplant 2014; suppl. 4: iv117-20.

  55. Takeuchi Y, Mishima E, Shima H, Akiyama Y, Suzuki C, Suzuki T, et al. Exonic Mutations in the SLC12A3 Gene Cause Exon Skipping and Premature Termination in Gitelman Syndrome. J Am Soc Nephrol Jul 24. Pii: 2013091013, 2014.

  56. Riveira-Munoz E, Chang Q, Godefroid N, Hoenderop JG, Bindels RJ, Dahan K, et al. Transcriptional and functional analyses of SLC12A3 mutations: new clues for the pathogenesis of Gitelman syndrome. J Am Soc Nephrol 2007; 18(4): 1271-83.

  57. Coto E, Rodriguez J, Jeck N, Alvarez V, Stone R, Loris C, et al. A new mutation (intron 9 +1 G>T) in the SLC12A3 gene is linked to Gitelman syndrome in Gypsies. Kidney Int 2004; 65(1): 25-9.

  58. Vargas-Poussou R, Dahan K, Kahila D, Venisse A, Riveira-Munoz E, Debaix H, et al. Spectrum of mutations in Gitelman syndrome. J Am Soc Nephrol 2011; 22(4): 693-703.

  59. Sabath E, Meade P, Berkman J, de Los Heros P, Moreno E, Bobadilla NA, et al. Pathophysiology of functional mutations of the thiazide-sensitive Na-Cl cotransporter in Gitelman disease. Am J Physiol Renal Physiol 2004; 287(2): F195-F203.

  60. de Jong JC, van der Vliet WA, van den Heuvel LPWJ, Willems PHGM, Knoers NVAM, Bindels RJM. Functional Expression of Mutations in the Human NaCl Cotransporter: Evidence for Impaired Routing Mechanisms in Gitelman’s Syndrome. J Am Soc Nephrol 2002; 13(6): 1442-8.

  61. Yang S-S, Fang Y-W, Tseng M-H, Chu P-Y, Yu I-S, Wu H-C, et al. Phosphorylation regulates NCC stability and transporter activity in vivo. J Am Soc Nephrol 2013; 24(10): 1587-97.




2020     |     www.medigraphic.com