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The acid-base regulation by renal proximal tubule

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DOI: 10.4236/ojmip.2013.34024    3,489 Downloads   5,779 Views  


The kidney plays quite an important role in the regulation of acid-base homeostasis. The dysfunction of renal acid-base regulation causes diseases such as developmental disorder, bone malformation, calcification of eye and brain, etc. In the kidney, this regulation is performed, to a considerable part, in the proximal tubule of the nephron. In the luminal side the key player is sodium-proton exchanger type 3 (NHE3), whereas sodium-bicarbonate cotransporter (NBCe1) plays the critical role in the basolateral side. In the cytoplasm there is carbonic anhydrase type 2 (CAII) that intermediates the conversion of CO2/ . Interestingly, in human, mutations have been found in NBCe1 and CAII but not in NHE3 so far. Mutations of NBCe1 lead to severe proximal renal tubular acidosis (pRTA) and other systemic manifestations. In animal model studies, however, the relative contribution of NHE3 to proximal tubule functions remains controversial. Recently, V-ATPase with renal specific subunits is suggested to have some roles in the regulation of proximal tubule functions. In this review, we will discuss the regulation of acid-base transport in the proximal tubule and the updates.

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The authors declare no conflicts of interest.

Cite this paper

Horita, S. , Yamazaki, O. , Nakamura, M. , Yamada, H. , Suzuki, M. and Seki, G. (2013) The acid-base regulation by renal proximal tubule. Open Journal of Molecular and Integrative Physiology, 3, 186-193. doi: 10.4236/ojmip.2013.34024.


[1] Bobulescu, I.A., Di Sole, F. and Moe, O.W. (2005) Na+/ H+ exchangers: Physiology and link to hypertension and organ ischemia. Current Opinion in Nephrology and Hypertension, 14, 485-494.
[2] Bobulescu, I.A. and Moe, O.W. (2009) Luminal Na+/H+ exchange in the proximal tubule. Pflügers Archiv, 458, 5-21.
[3] Orlowski, J. and Grinstein, S. (2007) Emerging roles of alkali cation/proton exchangers in organellar homeostasis. Current Opinion in Cell Biology, 19, 483-492.
[4] Slepkov, E.R., Rainey, J.K., Sykes, B.D. and Fliegel, L. (2007) Structural and functional analysis of the Na+/H+ exchanger. Biochemical Journal, 401, 623-633.
[5] Wang, D., King, S.M., Quill, T.A., Doolittle, L.K. and Garbers, D.L. (2003) A new sperm-specific Na+/H+ exchanger required for sperm motility and fertility. Nature Cell Biology, 5, 1117-1122.
[6] Pitts, R.F. and Lotspeich, W.D. (1946) Bicarbonate and the renal regulation of acid base balance. American Journal of Physiology, 147, 138-154.
[7] Pitts, R.F., Ayer, J.L., Schiess, W.A. and Miner, P. (1949) The renal regulation of acid-base balance in man. III. The reabsorption and excretion of bicarbonate. Journal of Clinical Investigation, 28, 35-44.
[8] Murer, H., Hopfer, U. and Kinne, R. (1976) Sodium/ proton antiport in brush-border-membrane vesicles isolated from rat small intestine and kidney. Biochemical Journal, 154, 597-604.
[9] Kinsella, J.L. and Aronson, P.S. (1980) Properties of the Na+-H+ exchanger in renal microvillus membrane vesicles. American Journal of Physiology, 238, F461-F469.
[10] Sardet, C., Franchi, A. and Pouysségur, J. (1989) Molecular cloning, primary structure, and expression of the human growth factor-activatable Na+/H+ antiporter. Cell, 56, 271-280.
[11] Biemesderfer, D., Pizzonia, J., Abu-Alfa, A., Exner, M., Reilly, R., Igarashi, P. and Aronson, P.S. (1993) NHE3: A Na+/H+ exchanger isoform of renal brush border. American Journal of Physiology, 265, F736-F742.
[12] Amemiya, M., Loffing, J., Lotscher, M., Kaissling, B., Alpern, R.J. and Moe, O.W. (1995) Expression of NHE-3 in the apical membrane of rat renal proximal tubule and thick ascending limb. Kidney International, 48, 1206-1215.
[13] Wu, M.S., Biemesderfer, D., Giebisch, G. and Aronson, P.S. (1996) Role of NHE3 in mediating renal brush border Na+-H+ exchange. Adaptation to metabolic acidosis. Journal of Biological Chemistry, 271, 32749-32752.
[14] Goyal, S., Vanden Heuvel, G. and Aronson, P.S. (2003) Renal expression of novel Na+/H+ exchanger isoform NHE8. American Journal of Physiology. Renal Physiology, 284, F467-F473.
[15] Goyal, S., Mentone, S. and Aronson, P.S. (2005) Immunolocalization of NHE8 in rat kidney. American Journal of Physiology. Renal Physiology, 288, F530-F538.
[16] Becker, A.M., Zhang, J., Goyal, S., Dwarakanath, V., Aronson, P.S., Moe, O.W. and Baum, M. (2007) Ontogeny of NHE8 in the rat proximal tubule. American Journal of Physiology. Renal Physiology, 293, F255-F261.
[17] Yun, C.H., Tse, C.M., Nath, S.K., Levine, S.A., Brant, S.R. and Donowitz, M. (1995) Mammalian Na+/H+ exchanger gene family: Structure and function studies. American Journal of Physiology, 269, G1-G11.
[18] Twombley, K., Gattineni, J., Bobulescu, I.A., Dwarakanath, V. and Baum, M. (2010) Effect of metabolic acidosis on neonatal proximal tubule acidification. American Journal of Physiology—Regulatory, Integrative and Comparative Physiology, 299, R1360-R1368.
[19] Schultheis, P.J., Clarke, L.L., Meneton, P., Miller, M.L., Soleimani, M., Gawenis, L.R., Riddle, T.M., Duffy, J.J., Doetschman, T., Wang, T., Giebisch, G., Aronson, P.S., Lorenz, J.N. and Shull, G.E. (1998) Renal and intestinal absorptive defects in mice lacking the NHE3 Na+/H+ ex- changer. Nature Genetics, 19, 282-285.
[20] Wang, T., Yang, C.L., Abbiati, T., Schultheis, P.J., Shull, G.E., Giebisch, G. and Aronson, P.S. (1999) Mechanism of proximal tubule bicarbonate absorption in NHE3 null mice. American Journal of Physiology, 277, F298-F302.
[21] Zhang, J., Bobulescu, I.A., Goyal, S., Aronson, P.S., Baum, M.G. and Moe, O.W. (2007) Characterization of Na+/H+ exchanger NHE8 in cultured renal epithelial cells. American Journal of Physiology. Renal Physiology, 293, F761-F766.
[22] Choi, J.Y., Shah, M., Lee, M.G., Schultheis, P.J., Shull, G.E., Muallem, S. and Baum, M. (2000) Novel amiloride-sensitive sodium-dependent proton secretion in the mouse proximal convoluted tubule. Journal of Clinical Investigation, 105, 1141-1146.
[23] Schultheis, P.J., Clarke, L.L., Meneton, P., Harline, M., Boivin, G.P., Stemmermann, G., Duffy, J.J., Doetschman, T., Miller, M.L. and Shull, G.E. (1998) Targeted disruption of the murine Na+/H+ exchanger isoform 2 gene causes reduced viability of gastric parietal cells and loss of net acid secretion. Journal of Clinical Investigation, 101, 1243-1253.
[24] Baum, M., Twombley, K., Gattineni, J., Joseph, C., Wang, L., Zhang, Q., Dwarakanath, V. and Moe, O.W. (2012) Proximal tubule Na+/H+ exchanger activity in adult NHE8-/-, NHE3-/-, and NHE3-/-/NHE8-/- mice. American Journal of Physiology. Renal Physiology, 303, F1495-F1502.
[25] Zachos, N.C., Tse, M. and Donowitz, M. (2005) Molecular physiology of intestinal Na+/H+ exchange. Annual Review of Physiology, 67, 411-443.
[26] Seki, G., Yamada, H., Horita, S., Suzuki, M., Yamazaki, O., Van Paesschen, W., Yang, S.S. and Lin, S.H. (2011) Physiological and pathophysiological roles of the electrogenic cotransporter NBCe1. Open Jour- nal of Molecular and Integrative Physiology, 1, 9-16.
[27] Romero, M.F., Hediger, M.A., Boulpaep, E.L. and Boron, W.F. (1997) Expression cloning and characterization of a renal electrogenic cotransporter. Nature, 387, 409-413.
[28] Igarashi, T., Inatomi, J., Sekine, T., Cha, S.H., Kanai, Y., Kunimi, M., Tsukamoto, K., Satoh, H., Shimadzu, M., Tozawa, F., Mori, T., Shiobara, M., Seki, G. and Endou, H. (1999) Mutations in SLC4A4 cause permanent isolated proximal renal tubular acidosis with ocular abnormalities. Nature Genetics, 23, 264-266.
[29] Romero, M.F., Fulton, C.M. and Boron, W.F. (2004) The SLC4 family of transporters. Pflügers Archiv, 447, 495-509.
[30] Liu, Y., Xu, J.Y., Wang, D.K., Wang, L. and Chen, L.M. (2011) Cloning and identification of two novel NBCe1 splice variants from mouse reproductive tract tissues: A comparative study of NCBT genes. Genomics, 98, 112-119.
[31] Romero, M.F. and Boron, W.F. (1999) Electrogenic cotransporters: Cloning and physiology. Annual Review of Physiology, 61, 699-723.
[32] Abuladze, N., Song, M., Pushkin, A., Newman, D., Lee, I. Nicholas, S. and Kurtz, I. (2000) Structural organization of the human NBC1 gene: kNBC1 is transcribed from an alternative promoter in intron 3. Gene, 251, 109-122.
[33] Bevensee, M.O., Schmitt, B.M., Choi, I., Romero, M.F. and Boron, W.F. (2000) An electrogenic Na(+)-HCO(-)(3) cotransporter (NBC) with a novel COOH-terminus, cloned from rat brain. American Journal of Physiology— Cell Physiology, 278, C1200-C1211.
[34] Shirakabe, K., Priori, G., Yamada, H., Ando, H., Horita, S., Fujita, T., Fujimoto, I., Mizutani, A., Seki, G. and Mikoshiba, K. (2006) IRBIT, an inositol 1,4,5-trisphosphate receptor-binding protein, specifically binds to and activates pancreas-type cotransporter 1 (pNBC1). Proceedings of the National Academy of Sciences of the United States of America, 103, 9542-9547.
[35] Yamazaki, O., Yamada, H., Suzuki, M., Horita, S., Shirai, A., Nakamura, M., Seki, G. and Fujita, T. (2011) Functional characterization of nonsynonymous single nucleo- tide polymorphisms in the electrogenic cotransporter NBCe1A. Pflügers Archiv, 461, 249-259.
[36] Zhu, Q., Lee, D.W. and Casey, J.R. (2003) Novel topo- logy in C-terminal region of the human plasma membrane anion exchanger, AE1. Journal of Biological Che- mistry, 278, 3112-3120.
[37] Boron, W.F. (2006) Acid-base transport by the renal proximal tubule. Journal of the American Society of Nephrology, 17, 2368-2382.
[38] Zhu, Q., Kao, L., Azimov, R., Abuladze, N., Newman, D., Pushkin, A., Liu, W., Chang, C. and Kurtz, I. (2010) Structural and functional characterization of the C-terminal transmembrane region of NBCe1-A. Journal of Biological Chemistry, 285, 37178-37187.
[39] Igarashi, T., Ishii, T., Watanabe, K., Hayakawa, H., Horio, K., Sone, Y. and Ohga, K. (1994) Persistent isolated proximal renal tubular acidosis—A systemic disease with a distinct clinical entity. Pediatric Nephrology, 8, 70-71.
[40] Horita, S., Yamada, H., Inatomi, J., Moriyama, N., Sekine, T., Igarashi, T., Endo, Y., Dasouki, M., Ekim, M., Al-Gazali, L., Shimadzu, M., Seki, G. and Fujita, T. (2005) Functional analysis of NBC1 mutants associated with proximal renal tubular acidosis and ocular abnormalities. Journal of the American Society of Nephrology, 16, 2270-2278.
[41] Dinour, D., Chang, M.H., Satoh, J., Smith, B.L., Angle, N., Knecht, A., Serban, I., Holtzman, E.J. and Romero, M.F. (2004) A novel missense mutation in the sodium bicarbonate cotransporter (NBCe1/SLC4A4) causes proximal tubular acidosis and glaucoma through ion trans- port defects. Journal of Biological Chemistry, 279, 52238-52246.
[42] Suzuki, M., Vaisbich, M.H., Yamada, H., Horita, S., Li, Y., Sekine, T., Moriyama, N., Igarashi, T., Endo, Y., Cardoso, T.P., de Sá, L.C., Koch, V.H., Seki, G. and Fujita, T. (2008) Functional analysis of a novel missense NBC1 mutation and of other mutations causing proximal renal tubular acidosis. Pflügers Archiv, 455, 583-593.
[43] Demirci, F.Y., Chang, M.H., Mah, T.S., Romero, M.F. and Gorin, M.B. (2006) Proximal renal tubular acidosis and ocular pathology: A novel missense mutation in the gene (SLC4A4) for sodium bicarbonate cotransporter protein (NBCe1). Molecular Vision, 12, 324-330.
[44] Igarashi, T., Inatomi, J., Sekine, T., Seki, G., Shimadzu, M., Tozawa, F., Takeshima, Y., Takumi, T., Takahashi, T., Yoshikawa, N., Nakamura, H. and Endou, H. (2001) Novel nonsense mutation in the cotransporter gene (SLC4A4) in a patient with permanent isolated proximal renal tubular acidosis and bilateral glaucoma. Journal of the American Society of Nephrology, 12, 713-718.
[45] Lo, Y.F., Yang, S.S., Seki, G., Yamada, H., Horita, S., Yamazaki, O., Fujita, T., Usui, T., Tsai, J.D., Yu, I.S., Lin, S.W. and Lin, S.H. (2011) Severe metabolic acidosis causes early lethality in NBC1 W516X knock-in mice as a model of human isolated proximal renal tubular acidosis. Kidney International, 79, 730-741.
[46] Inatomi, J., Horita, S., Braverman, N., Sekine, T., Yamada, H., Suzuki, Y., Kawahara, K., Moriyama, N., Kudo, A., Kawakami, H., Shimadzu, M., Endou, H., Fujita, T., Seki, G. and Igarashi, T. (2004) Mutational and functional analysis of SLC4A4 in a patient with proximal renal tubular acidosis. Pflügers Archiv, 448, 438-444.
[47] Suzuki, M., Van Paesschen, W., Stalmans, I., Horita, S., Yamada, H., Bergmans, B.A., Legius, E., Riant, F., De Jonghe, P., Li, Y., Sekine, T., Igarashi, T., Fujimoto, I., Mikoshiba, K., Shimadzu, M., Shiohara, M., Braverman, N., Al-Gazali, L., Fujita, T. and Seki, G. (2010) Defective membrane expression of the cotransporter NBCe1 is associated with familial migraine. Proceedings of the National Academy of Sciences of the United States of America, 107, 15963-15968.
[48] Zhu, Q., Kao, L., Azimov, R., Newman, D., Liu, W., Pushkin, A., Abuladze, N. and Kurtz, I. (2010) Topological location and structural importance of the NBCe1-A residues mutated in proximal renal tubular acidosis. Journal of Biological Chemistry, 285, 13416-13426.
[49] Gawenis, L.R., Bradford, E.M., Prasad, V., Lorenz, J.N., Simpson, J.E., Clarke, L.L., Woo, A.L., Grisham, C., Sanford, L.P., Doetschman, T., Miller, M.L. and Shull, G.E. (2007) Colonic anion secretory defects and metabolic acidosis in mice lacking the NBC1 cotransporter. Journal of Biological Chemistry, 282, 9042-9052.
[50] Welch, E.M., Barton, E.R., Zhuo, J., Tomizawa, Y., Friesen, W.J., Trifillis, P., Paushkin, S., Patel, M., Trotta, C.R., Hwang, S., Wilde, R.G., Karp, G., Takasugi, J., Chen, G., Jones, S., Ren, H., Moon, Y.C., Corson, D., Turpoff, A.A., Campbell, J.A., Conn, M.M., Khan, A., Almstead, N.G., Hedrick, J., Mollin, A., Risher, N., Weetall, M., Yeh, S., Branstrom, A.A., Colacino, J.M., Babiak, J., Ju, W.D., Hirawat, S., Northcutt, V.J., Miller, L.L., Spatrick, P., He, F., Kawana, M., Feng, H., Jacobson, A., Peltz, S.W. and Sweeney, H.L. (2007) PTC124 targets genetic disorders caused by nonsense mutations. Nature, 447, 87-91.
[51] Du, M., Liu, X., Welch, E.M., Hirawat, S., Peltz, S.W. and Bedwell, D.M. (2008) PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR-G542X nonsense allele in a CF mouse model. Proceedings of the National Academy of Sciences of the United States of America, 105, 2064-2069.
[52] Wagner, C.A., Finberg, K.E., Breton, S., Marshansky, V., Brown, D. and Geibel, J.P. (2004) Renal vacuolar H+-ATPase. Physiological Reviews, 84, 1263-1314.
[53] Nishi, T. and Forgac, M. (2002) The vacuolar (H+)-AT-Pases—Nature’s most versatile proton pumps. Nature Reviews Molecular Cell Biology, 3, 94-103.
[54] Brody, L.C., Abel, K.J., Castilla, L.H., Couch, F.J., McKinley, D.R., Yin, G., Ho, P.P., Merajver, S., Chandrasekharappa, S.C. and Xu, J. (1995) Construction of a transcription map surrounding the BRCA1 locus of human chromosome 17. Genomics, 25, 238-247.
[55] Peng, S.B., Crider, B.P., Xie, X.S., Stone, D.K. (1994) Alternative mRNA splicing generates tissue-specific isoforms of 116-kDa polypeptide of vacuolar proton pump. Journal of Biological Chemistry, 269, 17262-17266.
[56] Peng, S.B., Li, X., Crider, B.P., Zhou, Z., Andersen, P., Tsai, S.J., Xie, X.S. and Stone, D.K. (1999) Identification and reconstitution of an isoform of the 116-kDa subunit of the vacuolar proton translocating ATPase. Journal of Biological Chemistry, 274, 2549-2555.
[57] Frattini, A., Orchard, P.J., Sobacchi, C., Giliani, S., Abinun, M., Mattsson, J.P., Keeling, D.J., Andersson, A.K., Wallbrandt, P., Zecca, L., Notarangelo, L.D., Vezzoni, P. and Villa, A. (2000) Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nature Genetics, 25, 343-346.
[58] Smith, A.N., Borthwick, K.J. and Karet, F.E. (2002) Molecular cloning and characterization of novel tissue-specific isoforms of the human vacuolar H(+)-ATPase C, G and d subunits, and their evaluation in autosomal recessive distal renal tubular acidosis. Gene, 297, 169-177.
[59] Karet, F.E., Finberg, K.E., Nelson, R.D., Nayir, A., Mocan, H., Sanjad, S.A., Rodriguez-Soriano, J., Santos, F., Cremers, C.W., Di Pietro, A., Hoffbrand, B.I., Winiarski, J., Bakkaloglu, A., Ozen, S., Dusunsel, R., Goodyer, P., Hulton, S.A., Wu, D.K., Skvorak, A.B., Morton, C.C., Cunningham, M.J., Jha, V. and Lifton, R.P. (1999) Mutations in the gene encoding B1 subunit of H+-ATPase cause renal tubular acidosis with sensorineural deafness. Nature Genetics, 21, 84-90.
[60] Nelson, R.D., Guo, X.L., Masood, K., Brown, D., Kalkbrenner, M. and Gluck, S. (1992) Selectively amplified expression of an isoform of the vacuolar H(+)-ATPase 56-kilodalton subunit in renal intercalated cells. Proceedings of the National Academy of Sciences of the United States of America, 89, 3541-3545.
[61] van Hille, B., Richener, H., Schmid, P., Puettner, I., Green, J.R. and Bilbe, G. (1994) Heterogeneity of vacuolar H(+)-ATPase: differential expression of two human subunit B isoforms. Biochemical Journal, 303, 191-198.
[62] Bernasconi, P., Rausch, T., Struve, I., Morgan, L. and Taiz, L. (1990) An mRNA from human brain encodes an isoform of the B subunit of the vacuolar H(+)-ATPase. Journal of Biological Chemistry, 265, 17428-17431.
[63] Karet, F.E. (2005) Physiological and metabolic implications of V-ATPase isoforms in the kidney. Journal of Bioenergetics and Biomembranes, 37, 425-429.
[64] Smith, A.N., Finberg, K.E., Wagner, C.A., Lifton, R.P., Devonald, M.A., Su, Y. and Karet, F.E. (2001) Molecular cloning and characterization of Atp6n1b: A novel fourth murine vacuolar H+-ATPase a-subunit gene. Journal of Biological Chemistry, 276, 42382-42388.
[65] Smith, A.N., Skaug, J., Choate, K.A., Nayir, A., Bakka- loglu, A., Ozen, S., Hulton, S.A., Sanjad, S.A., Al-Sabban, E.A., Lifton, R.P., Scherer, S.W. and Karet, F.E. (2000) Mutations in ATP6N1B, encoding a new kidney vacuolar proton pump 116-kD subunit, cause recessive distal renal tubular acidosis with preserved hearing. Nature Genetics, 26, 71-75.
[66] Stover, E.H., Borthwick, K.J., Bavalia, C., Eady, N., Fritz, D.M., Rungroj, N., Giersch, A.B., Morton, C.C., Axon, P.R., Akil, I., Al-Sabban, E.A., Baguley, D.M., Bianca, S., Bakkaloglu, A., Bircan, Z., Chauveau, D., Clermont, M.J., Guala, A., Hulton, S.A., Kroes, H., Li Volti, G., Mir, S., Mocan, H., Nayir, A., Ozen, S., Rodriguez Soriano, J., Sanjad, S.A., Tasic, V., Taylor, C.M., Topaloglu, R., Smith, A.N. and Karet, F.E. (2002) Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss. Journal of Medical Genetics, 39, 796-803.
[67] Norgett, E.E., Golder, Z.J., Lorente-Cánovas, B., Ingham, N., Steel, K.P. and Frankl, F.E. (2012) Atp6v0a4 knock-out mouse is a model of distal renal tubular acidosis with hearing loss, with additional extrarenal phenotype. Proceedings of the National Academy of Sciences of the United States of America, 109, 13775-13780.
[68] Hennings, J.C., Picard, N., Huebner, A.K., Stauber, T., Maier, H., Brown, D., Jentsch, T.J, Vargas-Poussou, R., Eladari, D. and Hübner, C.A. (2012) A mouse model for distal renal tubular acidosis reveals a previously unrecognized role of the V-ATPase a4 subunit in the proximal tubule. EMBO Molecular Medicine, 4, 1057-1071.
[69] Everett, L.A., Belyantseva, I.A., Noben-Trauth, K., Can- tos, R., Chen, A., Thakkar, S.I., Hoogstraten-Miller, S.L., Kachar, B., Wu, D.K. and Green, E.D. (2001) Targeted disruption of mouse Pds provides insight about the innerear defects encountered in Pendred syndrome. Human Molecular Genetics, 10, 153-161.
[70] Everett, L.A., Glaser, B., Beck, J.C., Idol, J.R., Buchs, A., Heyman, M., Adawi, F., Hazani, E., Nassir, E., Baxevanis, A.D., Sheffield, V.C. and Green, E.D. (1997) Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nature Genetics, 17, 411-422.
[71] Wagner, C.A., Mohebbi, N., Capasso, G. and Geibel, J.P. (2011) The anion exchanger pendrin (SLC26A4) and renal acid-base homeostasis. Cellular Physiology and Biochemistry, 28, 497-504.
[72] Wangemann, P. (2011) The role of pendrin in the development of the murine inner ear. Cellular Physiology and Biochemistry, 28, 527-534.

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