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Current Hypertension Reports

, 18:71 | Cite as

The Renal Sodium Bicarbonate Cotransporter NBCe2: Is It a Major Contributor to Sodium and pH Homeostasis?

  • Robin A. FelderEmail author
  • Pedro A. Jose
  • Peng Xu
  • John J. Gildea
Hypertension and the Kidney (RM Carey, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Hypertension and the Kidney

Abstract

The sodium bicarbonate cotransporter (NBCe2, aka NBC4) was originally isolated from the human testis and heart (Pushkin et al. IUBMB Life 50:13–19, 2000). Subsequently, NBCe2 was found in diverse locations where it plays a role in regulating sodium and bicarbonate transport, influencing intracellular, extracellular, interstitial, and ultimately plasma pH (Boron et al. J Exp Biol. 212:1697–1706, 2009; Parker and Boron, Physiol Rev. 93:803–959, 2013; Romero et al. Mol Asp Med. 34:159–182, 2013). NBCe2 is located in human and rodent renal-collecting duct and proximal tubule. While much is known about the two electrogenic sodium bicarbonate cotransporters, NBCe1 and NBCe2, in the regulation of sodium homeostasis and pH balance in the rodent kidney, little is known about their roles in human renal physiology. NBCe2 is located in the proximal tubule Golgi apparatus under basal conditions and then disperses throughout the cell, but particularly into the apical membrane microvilli, during various maneuvers that increase intracellular sodium. This review will summarize our current understanding of the distribution and function of NBCe2 in the human kidney and how genetic variants of its gene, SLC4A5, contribute to salt sensitivity of blood pressure.

Keywords

Renal sodium Sodium bicarbonate cotransporter pH homeostasis NBCe2 Salt sensitivity of blood pressure 

Notes

Compliance with Ethical Standards

Conflict of Interest

Drs. Felder, Jose, Xu, and Gildea declare no conflicts of interest relevant to this manuscript.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Wagner CA, Finberg KE, Breton S, Marshansky V, Brown D, Geibel JP. Renal vacuolar h + −atpase. Physiol Rev. 2004;84:1263–314.CrossRefPubMedGoogle Scholar
  2. 2.••
    Parker MD, Boron WF. The divergence, actions, roles, and relatives of sodium-coupled bicarbonate transporters. Physiol Rev. 2013;93:803–959. This paper is the most comprehensive review of sodium-coupled bicarbonate transporters.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.••
    Romero MF, Chen AP, Parker MD, Boron WF. The slc4 family of bicarbonate (hco3) transporters. Mol Asp Med. 2013;34:159–82. This paper is also a good comprehensive review of  bicarbonate transporters.CrossRefGoogle Scholar
  4. 4.
    Boron WF, Boulpaep EL. Intracellular pH regulation in the renal proximal tubule of the salamander. Basolateral hco3- transport. J Gen Physiol. 1983;81:53–94.CrossRefPubMedGoogle Scholar
  5. 5.
    Pushkin A, Abuladze N, Newman D, Lee I, Xu G, Kurtz I. Two c-terminal variants of nbc4, a new member of the sodium bicarbonate cotransporter family: cloning, characterization, and localization. IUBMB Life. 2000;50:13–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Schmitt BM, Biemesderfer D, Romero MF, Boulpaep EL, Boron WF. Immunolocalization of the electrogenic na + −hco-3 cotransporter in mammalian and amphibian kidney. Am J Physiol. 1999;276:F27–38.PubMedGoogle Scholar
  7. 7.•
    Skelton LA, Boron WF, Zhou Y. Acid–base transport by the renal proximal tubule. J Nephrol. 2010;23 Suppl 16:S4–18. This paper is a good summary of acid-base transport.Google Scholar
  8. 8.
    Maunsbach AB, Vorum H, Kwon TH, Nielsen S, Simonsen B, Choi I, et al. Immunoelectron microscopic localization of the electrogenic na/hco(3) cotransporter in rat and ambystoma kidney. J Am Soc Nephrol. 2000;11:2179–89.PubMedGoogle Scholar
  9. 9.
    Boron WF, Chen L, Parker MD. Modular structure of sodium-coupled bicarbonate transporters. J Exp Biol. 2009;212:1697–706.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.•
    Gildea JJ, Xu P, Carlson JM, Gaglione RT, Bigler Wang D, Kemp BA, et al. The sodium-bicarbonate cotransporter nbce2 (slc4a5) expressed in human renal proximal tubules shows increased apical expression under high-salt conditions. Am J Physiol Regul Integr Comp Physiol. 2015;309:R1447–59. This paper from our group demonstrates the presence of NBCe2 on the apical membrane of the human renal proximal tubule.CrossRefPubMedGoogle Scholar
  11. 11.••
    Gildea JJ, Xu P, Carlson J, Gaglione R, Wang DB, Kemp B, Reyes C, McGrath H, Carey R, Jose PA, Felder RA. Role of human renal proximal tubule sodium bicarbonate cotransporter nbce2 (slc4a5) in salt sensitivity of blood pressure. American Heart Council for High Blood Pressure Research, 2015. Poster Abstract 242 http://my.americanheart.org/idc/groups/ahamahpublic/@wcm/@sop/@scon/documents/downloadable/ucm_477293.pdf:PA242. This abstract is the first demonstration of a link between polymorphisms in SLC4A5 and aberrant renal sodium regulation.
  12. 12.
    Faggio C, Torre A, Lando G, Sabatino G, Trischitta F. Carbonate precipitates and bicarbonate secretion in the intestine of sea bass, Dicentrarchus labrax. J Comp Physiol B. 2011;181:517–25.Google Scholar
  13. 13.
    Choi I, Aalkjaer C, Boulpaep EL, Boron WF. An electroneutral sodium/bicarbonate cotransporter nbcn1 and associated sodium channel. Nature. 2000;405:571–5.CrossRefPubMedGoogle Scholar
  14. 14.
    Wang Z, Wang T, Petrovic S, Tuo B, Riederer B, Barone S, et al. Renal and intestinal transport defects in slc26a6-null mice. Am J Physiol Cell Physiol. 2005;288:C957–65.CrossRefPubMedGoogle Scholar
  15. 15.
    Simão S, Gomes P, Pinho MJ, Soares-da-Silva P. Identification of slc26a transporters involved in the cl-/hco3 exchange in proximal tubular cells from wky and shr. Life Sci. 2013;93:435–40.CrossRefPubMedGoogle Scholar
  16. 16.
    Simão S, Gomes P, Jose PA, Soares-da-Silva P. Increased responsiveness to jnk1/2 mediates the enhanced h2o2-induced stimulation of cl-/hco3- exchanger activity in immortalized renal proximal tubular epithelial cells from the shr. Biochem Pharmacol. 2010;80:913–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Simão S, Pedrosa R, Hopfer U, Mount DB, Jose PA, Soares-da-Silva P. Short-term regulation of the cl-/hco3(−) exchanger in immortalized shr proximal tubular epithelial cells. Biochem Pharmacol. 2008;75:2224–33.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Zhuo JL, Li XC. Proximal nephron. Compr Physiol. 2013;3:1079–123.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Aalkjaer C, Boedtkjer E, Choi I, Lee S. Cation-coupled bicarbonate transporters. Compr Physiol. 2014;4:1605–37.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Ohana E, Yang D, Shcheynikov N, Muallem S. Diverse transport modes by the solute carrier 26 family of anion transporters. J Physiol. 2009;587:2179–85.CrossRefPubMedGoogle Scholar
  21. 21.
    Palmer LG, Schnermann J. Integrated control of Na transport along the nephron. Clin J Am Soc Nephrol. 2015;10:676–87.Google Scholar
  22. 22.
    Guyton A, Hall J, Coleman T. The dominant role of the kidneys in long-term arterial pressure regulation in normal and hypertensive states. New York: Raven; 1995.Google Scholar
  23. 23.
    Banday AA, Lokhandwala MF. Novel gastro-renal axis and sodium regulation during hypertension. Hypertension. 2013;62:834–5.CrossRefPubMedGoogle Scholar
  24. 24.
    Chen Y, Asico LD, Zheng S, Villar VA, He D, Zhou L, et al. Gastrin and D1 dopamine receptor interact to induce natriuresis and diuresis. Hypertension. 2013;62:927–33.Google Scholar
  25. 25.
    Jose PA, Yang Z, Zeng C, Felder RA. The importance of the gastrorenal axis in the control of body sodium homeostasis. Exp Physiol. 2016;101:465–70.CrossRefPubMedGoogle Scholar
  26. 26.
    Spencer AG, Labonte ED, Rosenbaum DP, Plato CF, Carreras CW, Leadbetter MR, et al. Intestinal inhibition of the Na+/H+ exchanger 3 prevents cardiorenal damage in rats and inhibits Na+ uptake in humans. Sci Transl Med. 2014;6, 227ra236.Google Scholar
  27. 27.
    Coffman TM, Crowley SD. Kidney in hypertension: guyton redux. Hypertension. 2008;51:811–6.CrossRefPubMedGoogle Scholar
  28. 28.
    Jose PA, Eisner GM, Felder RA. Regulation of blood pressure by dopamine receptors. Nephron Physiol. 2003;95:p19–27.CrossRefPubMedGoogle Scholar
  29. 29.••
    Xu J, Wang Z, Barone S, Petrovic M, Amlal H, Conforti L, et al. Expression of the Na+;HCO−3 cotransporter nbc4 in rat kidney and characterization of a novel NBC4 variant. Am J Physiol Renal Physiol. 2003;284:F41–50. This paper is the first demonstration of SLC4A5 mRNA in the kidney.Google Scholar
  30. 30.
    Damkier HH, Nielsen S, Praetorius J. Molecular expression of SLC4-derived Na+ −dependent anion transporters in selected human tissues. Am J Physiol Regul Integr Comp Physiol. 2007;293:R2136–46.Google Scholar
  31. 31.
    Yang L, Leong PK, Chen JO, Patel N, Hamm-Alvarez SF, McDonough AA. Acute hypertension provokes internalization of proximal tubule NHE3 without inhibition of transport activity. Am J Physiol Renal Physiol. 2002;282:F730–40.Google Scholar
  32. 32.
    Burnham CE, Flagella M, Wang Z, Amlal H, Shull GE, Soleimani M. Cloning, renal distribution, and regulation of the rat Na+-HCO3- cotransporter. Am J Physiol. 1998;274:F1119–26.Google Scholar
  33. 33.
    Kurtz I, Zhu Q. Proximal renal tubular acidosis mediated by mutations in NBCe1-A: unraveling the transporter’s structure-functional properties. Front Physiol. 2013;4:350.Google Scholar
  34. 34.
    Gröger N, Vitzthum H, Fröhlich H, Krüger M, Ehmke H, Braun T, et al. Targeted mutation of SLC4A5 induces arterial hypertension and renal metabolic acidosis. Hum Mol Genet. 2012;21:1025–36.Google Scholar
  35. 35.
    Wen D, Sansom SC. Physiological role of NBCe2 in the regulation of electrolyte transport in the distal nephron. Am J Physiol Renal Physiol. 2015;309:F489–91.Google Scholar
  36. 36.
    Yamada H, Yamazaki S, Moriyama N, Hara C, Horita S, Enomoto Y, et al. Localization of NBC-1 variants in human kidney and renal cell carcinoma. Biochem Biophys Res Commun. 2003;310:1213–8.Google Scholar
  37. 37.
    Aviv A, Hollenberg NK, Weder A. Urinary potassium excretion and sodium sensitivity in blacks (response: reinterpreting sodium-potassium data in salt sensitivity hypertension: a prospective debate). Hypertension. 2005;43:707–13.CrossRefGoogle Scholar
  38. 38.
    Doris PA. Renal proximal tubule sodium transport and genetic mechanisms of essential hypertension. J Hypertens. 2000;18:509–19.CrossRefPubMedGoogle Scholar
  39. 39.
    Ortiz PA, Garvin JL. Intrarenal transport and vasoactive substances in hypertension. Hypertension. 2001;38:621–4.CrossRefPubMedGoogle Scholar
  40. 40.
    Khalil RA. Dietary salt and hypertension: new molecular targets add more spice. Am J Physiol Regul Integr Comp Physiol. 2006;290:R509–13.CrossRefPubMedGoogle Scholar
  41. 41.
    Lifton RP, Gharavi AG, Geller DS. Molecular mechanisms of human hypertension. Cell. 2001;104:545–56.CrossRefPubMedGoogle Scholar
  42. 42.••
    Barkley RA, Chakravarti A, Cooper RS, Ellison RC, Hunt SC, Province MA, et al. Positional identification of hypertension susceptibility genes on chromosome 2. Hypertension. 2004;43:477–82. This paper demonstrates a genetic link between chromosome 2, the locationi of SLC4A5, and hypertension.Google Scholar
  43. 43.••
    Carey RM, Schoeffel CD, Gildea JJ, Jones JE, McGrath HE, Gordon LN, et al. Salt sensitivity of blood pressure is associated with polymorphisms in the sodium-bicarbonate cotransporter. Hypertension. 2012;60:1359–66. This paper from our group demonstrates a strong association between two SNPs in SLC4A5 and salt sensitivity of blood pressure.Google Scholar
  44. 44.••
    Hunt SC, Xin Y, Wu LL, Cawthon RM, Coon H, Hasstedt SJ, et al. Sodium bicarbonate cotransporter polymorphisms are associated with baseline and 10-year follow-up blood pressures. Hypertension. 2006;47:532–6. This paper corroborates the findings of Carey et al in reference 43.Google Scholar
  45. 45.••
    Stutz AM, Teran-Garcia M, Rao DC, Rice T, Bouchard C, Rankinen T. Functional identification of the promoter of SLC4a5, a gene associated with cardiovascular and metabolic phenotypes in the heritage family study. Eur J Hum Genet. 2009;17:1481–9. This paper corroborates the work of Carey et al in reference 43 and the work of Hunt in reference 44.Google Scholar
  46. 46.
    Taylor JY, Maddox R, Wu CY. Genetic and environmental risks for high blood pressure among African American mothers and daughters. Biol Res Nurs. 2009;11:53–65.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Padmanabhan S, Menni C, Lee WK, Laing S, Brambilla P, Sega R, et al. The effects of sex and method of blood pressure measurement on genetic associations with blood pressure in the PAMELA study. J Hypertens. 2010;28:465–77.Google Scholar
  48. 48.
    Pedrosa R, Gonçalves N, Hopfer U, Jose PA, Soares-da-Silva P. Activity and regulation of Na+-HCO3- cotransporter in immortalized spontaneously hypertensive rat and Wistar-Kyoto rat proximal tubular epithelial cells. Hypertension. 2007;49:1186–93.Google Scholar
  49. 49.
    Beach RE, DuBose TD. Adrenergic regulation of (Na+-K+)-ATPase activity in proximal tubules of spontaneously hypertensive rats. Kidney Int. 1990;38:402–8.Google Scholar
  50. 50.
    Hayashi M, Yoshida T, Monkawa T, Yamaji Y, Sato S, Saruta T. Na+/H + −exchanger 3 activity and its gene in the spontaneously hypertensive rat kidney. J Hypertens. 1997;15:43–8.Google Scholar
  51. 51.
    Xu J, Li XX, Albrecht FE, Hopfer U, Carey RM, Jose PA. Dopamine(1) receptor, G(salpha), and Na(+)-H(+) exchanger interactions in the kidney in hypertension. Hypertension. 2000;36:395–9.Google Scholar
  52. 52.
    Yao LP, Li XX, Yu PY, Xu J, Asico LD, Jose PA. Dopamine D1 receptor and protein kinase C isoforms in spontaneously hypertensive rats. Hypertension. 1998;32:1049–53.Google Scholar
  53. 53.
    Ehret GB, Munroe PB, Rice KM, Bochud M, Johnson AD, Chasman DI, et al. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature. 2011;478:103–9.CrossRefPubMedGoogle Scholar
  54. 54.
    Forman JP, Rifas-Shiman SL, Taylor EN, Lane K, Gillman MW. Association between the serum anion gap and blood pressure among patients at Harvard Vanguard Medical Associates. J Hum Hypertens. 2008;22:122–5.Google Scholar
  55. 55.
    Farwell WR, Taylor EN. Serum anion gap, bicarbonate and biomarkers of inflammation in healthy individuals in a national survey. CMAJ. 2010;182:137–41.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Abramowitz MK, Hostetter TH, Melamed ML. Lower serum bicarbonate and a higher anion gap are associated with lower cardiorespiratory fitness in young adults. Kidney Int. 2012;81:1033–42.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Sharma AM, Cetto C, Schorr U, Spies KP, Distler A. Renal acid–base excretion in normotensive salt-sensitive humans. Hypertension. 1993;22:884–90.CrossRefPubMedGoogle Scholar
  58. 58.
    Wen D, Yuan Y, Warner PC, Wang B, Cornelius RJ, Wang-France J, et al. Increased epithelial sodium channel activity contributes to hypertension caused by Na+-HCO3- cotransporter electrogenic 2 deficiency. Hypertension. 2015;66:68–74.Google Scholar
  59. 59.
    Elijovich F, Weinberger MH, Anderson CAM, Appel LJ, Bursztyn M, Cook NR, Dart RA, Newton-Cheh CH, Sacks FM, Laffer CL, American Heart Association Professional and Public Education Committee of the Council on Hypertension; Council on Functional Genomics and Translational Biology; and Stroke Council. Salt sensitivity of blood pressure: a scientific statement from the American Heart Association. Hypertension. 2016;68:e7–e46.Google Scholar
  60. 60.
    Weinberger MH, Miller JZ, Luft FC, Grim CE, Fineberg NS. Definitions and characteristics of sodium sensitivity and blood pressure resistance. Hypertension. 1986;8:II127–34.CrossRefPubMedGoogle Scholar
  61. 61.
    Weinberger MH, Fineberg NS, Fineberg SE, Weinberger M. Salt sensitivity, pulse pressure, and death in normal and hypertensive humans. Hypertension. 2001;37:429–32.CrossRefPubMedGoogle Scholar
  62. 62.
    Pojoga LH, Underwood PC, Goodarzi MO, Williams JS, Adler GK, Jeunemaitre X, et al. Variants of the caveolin-1 gene: a translational investigation linking insulin resistance and hypertension. J Clin Endocrinol Metab. 2011;96:E1288–92.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.•
    Taylor JY, Wu CY, Darling D, Sun YV, Kardia SL, Jackson JS. Gene-environment effects of SLC4a5 and skin color on blood pressure among african american women. Ethn Dis. 2012;22:155–61. This paper links polymorphisms of SLC4A5 with blood presssure regulation.Google Scholar
  64. 64.
    Lynn KS, Li LL, Lin YJ, Wang CH, Sheng SH, Lin JH, et al. A neural network model for constructing endophenotypes of common complex diseases: an application to male young-onset hypertension microarray data. Bioinformatics. 2009;25:981–8.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Guo L, Liu F, Chen S, Yang X, Huang J, He J, et al. Common variants in the Na(+)-coupled bicarbonate transporter genes and salt sensitivity of blood pressure: The gensalt study. J Hum Hypertens. 2016;30:543–8.Google Scholar
  66. 66.••
    Oh YS, Appel LJ, Galis ZS, Hafler DA, He J, Hernandez AL, et al. National heart, lung, and blood institute working group report on salt in human health and sickness: building on the current scientific evidence. Hypertension. 2016;68:281–8. This review covers the importance of sodium reduction in the human diet.CrossRefPubMedGoogle Scholar
  67. 67.
    de Wardener HE, He FJ, MacGregor GA. Plasma sodium and hypertension. Kidney Int. 2004;66:2454–66.CrossRefPubMedGoogle Scholar
  68. 68.
    Stocker SD, Monahan KD, Browning KN. Neurogenic and sympathoexcitatory actions of nacl in hypertension. Curr Hypertens Rep. 2013;15:538–46.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Titze J. Sodium balance is not just a renal affair. Curr Opin Nephrol Hypertens. 2014;23:101–5.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Thiagarajan RD, Georgas KM, Rumballe BA, Lesieur E, Chiu HS, Taylor D, et al. Identification of anchor genes during kidney development defines ontological relationships, molecular subcompartments and regulatory pathways. PLoS One. 2011;6, e17286.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Gallegos TF, Martovetsky G, Kouznetsova V, Bush KT, Nigam SK. Organic anion and cation slc22 “drug” transporter (oat1, oat3, and oct1) regulation during development and maturation of the kidney proximal tubule. PLoS One. 2012;7, e40796.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Hahn-Windgassen A, Van Gilst MR. The Caenorhabditis elegans HNF4alpha homolog, NHR-31, mediates excretory tube growth and function through coordinate regulation of the vacuolar ATPase. PLoS Genet. 2009;5, e1000553.Google Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Robin A. Felder
    • 1
    Email author
  • Pedro A. Jose
    • 2
  • Peng Xu
    • 1
  • John J. Gildea
    • 1
  1. 1.Department of PathologyThe University of VirginiaCharlottesvilleUSA
  2. 2.Department of Medicine, Division of Renal Diseases and Hypertension and Department of Pharmacology and PhysiologyThe George Washington UniversityWashingtonUSA

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