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CFTR and TNR-CFTR expression and function in the kidney

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Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) is abundantly expressed in the kidney. CFTR mRNA is detected in all nephron segments of rats and humans and its expression is higher in the renal cortex and outer medulla than in the inner medulla. CFTR protein is detected at the apical surface of both proximal and distal tubules of rat kidney but not in the outer medullary collecting ducts. The localization of CFTR in the proximal tubules is compatible with that of endosomes, suggesting that CFTR might regulate pH in endocytic vesicles by equilibrating H+ accumulation due to H+-ATPase activity. Many studies have also demonstrated that CFTR also regulates channel pore opening and the transport of sodium, chloride and potassium. The kidneys also express a CFTR splicing variant, called TNR-CFTR, in a tissue-specific manner, primarily in the renal medulla. This splicing variant conserves the functional characteristics of wild-type CFTR. The functional significance of TNR-CFTR remains to be elucidated, but our group proposes that TNR-CFTR may have a basic function in intracellular organelles, rather than in the plasma membrane. Also, this splicing variant is able to partially substitute CFTR functions in the renal medulla of Cftr-/- mice and CF patients. In this review we discuss the major functions that have been proposed for CFTR and TNR-CFTR in the kidney.

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References

  • Aguilar-Bryan L, Clement JP, Gonzalez G, Kunjilwar K, Babenko A, Bryan J (1998) Toward understanding the assembly and structure of KATP channels. Physiol Rev 78:227–245

    CAS  PubMed  Google Scholar 

  • Aleksandrov L, Aleksandrov AA, Chang XB, Riordan JR (2002) The first nucleotide binding domain of cystic fibrosis transmembrane conductance regulator is a site of stable nucleotide interaction, whereas the second is a site of rapid turnover. J Biol Chem 277:15419–15425

    Article  CAS  PubMed  Google Scholar 

  • Basso C, Vergani P, Nairn AC, Gadsby DC (2003) Prolonged nonhydrolytic interaction of nucleotide with CFTR's NH2-terminal nucleotide binding domain and its role in channel gating. J Gen Physiol 122:333–348

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bear CE, Li CH, Kartner N, Bridges RJ, Jensen TJ, Ramjeesingh M, Riordan JR (1992) Purification and functional reconstitution of the cystic fibrosis transmembrane conductance regulator (CFTR). Cell 68:809–818

    Article  CAS  PubMed  Google Scholar 

  • Berend K, van Hulsteijn LH, Gans RO (2012) Chloride: the queen of electrolytes? Eur J Intern Med 23:203–211

    Article  CAS  PubMed  Google Scholar 

  • Bradbury NA (1999) Intracellular CFTR: localization and function. Physiol Rev 79:S175–S191

    CAS  PubMed  Google Scholar 

  • Briel M, Greger R, Kunzelmann K (1998) Cl– transport by cystic fibrosis transmembrane conductance regulator (CFTR) contributes to the inhibition of epithelial Na+ channels (ENaCs) in Xenopus oocytes co-expressing CFTR and ENaC. J Physiol 508(Pt 3):825–836

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Carraro-Lacroix LR, Lessa LM, Bezerra CN, Pessoa TD, Souza-Menezes J, Morales MM, Girardi AC, Malnic G (2010) Role of CFTR and ClC-5 in modulating vacuolar H+-ATPase activity in kidney proximal tubule. Cell Physiol Biochem 26:563–576

    Article  CAS  PubMed  Google Scholar 

  • Chen TY, Hwang TC (2008) CLC-0 and CFTR: chloride channels evolved from transporters. Physiol Rev 88:351–387

    Article  CAS  PubMed  Google Scholar 

  • Christensen EI, Birn H (2002) Megalin and cubilin: multifunctional endocytic receptors. Nat Rev Mol Cell Biol 3:256–266

    CAS  PubMed  Google Scholar 

  • Christensen EI, Devuyst O, Dom G, Nielsen R, Van der Smissen P, Verroust P, Leruth M, Guggino WB, Courtoy PJ (2003) Loss of chloride channel ClC-5 impairs endocytosis by defective trafficking of megalin and cubilin in kidney proximal tubules. Proc Natl Acad Sci USA 100:8472–8477

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Collins FS (1992) Cystic fibrosis: molecular biology and therapeutic implications. Science 256:774–779

    Article  CAS  PubMed  Google Scholar 

  • Collins FS, Riordan JR, Tsui LC (1990) The cystic fibrosis gene: isolation and significance. Hosp Pract (Off Ed) 25:47–57

    CAS  Google Scholar 

  • Crawford I, Maloney PC, Zeitlin PL, Guggino WB, Hyde SC, Turley H, Gatter KC, Harris A, Higgins CF (1991) Immunocytochemical localization of the cystic fibrosis gene product CFTR. Proc Natl Acad Sci USA 88:9262–9266

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Cuffe JE, Bielfeld-Ackermann A, Thomas J, Leipziger J, Korbmacher C (2000) ATP stimulates Cl– secretion and reduces amiloride-sensitive Na+ absorption in M-1 mouse cortical collecting duct cells. J Physiol 524(Pt 1):77–90

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • de Andrade Pinto AC, Barbosa CM, Ornellas DS, Novaira HJ, de Souza-Menezes J, Ortiga-Carvalho TM, Fong P, Morales MM (2007) Thyroid hormones stimulate renal expression of CFTR. Cell Physiol Biochem 20:83–90

    PubMed  Google Scholar 

  • Devor DC, Pilewski JM (1999) UTP inhibits Na+ absorption in wild-type and DeltaF508 CFTR-expressing human bronchial epithelia. Am J Physiol 276:C827–C837

    CAS  PubMed  Google Scholar 

  • Devuyst O, Burrow CR, Schwiebert EM, Guggino WB, Wilson PD (1996) Developmental regulation of CFTR expression during human nephrogenesis. Am J Physiol 271:F723–F735

    CAS  PubMed  Google Scholar 

  • Fuller CM, Benos DJ (1992) CFTR! Am J Physiol 263:C267–C286

    CAS  PubMed  Google Scholar 

  • Fulmer SB, Schwiebert EM, Morales MM, Guggino WB, Cutting GR (1995) Two cystic fibrosis transmembrane conductance regulator mutations have different effects on both pulmonary phenotype and regulation of outwardly rectified chloride currents. Proc Natl Acad Sci USA 92:6832–6836

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gadsby DC, Vergani P, Csanady L (2006) The ABC protein turned chloride channel whose failure causes cystic fibrosis. Nature 440:477–483

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Giebisch G (1998) Renal potassium transport: mechanisms and regulation. Am J Physiol 274:F817–F833

    CAS  PubMed  Google Scholar 

  • Greger R (1985) Ion transport mechanisms in thick ascending limb of Henle's loop of mammalian nephron. Physiol Rev 65:760–797

    CAS  PubMed  Google Scholar 

  • Hebert SC, Andreoli TE (1984) Control of NaCl transport in the thick ascending limb. Am J Physiol 246:F745–F756

    CAS  PubMed  Google Scholar 

  • Huber S, Braun G, Burger-Kentischer A, Reinhart B, Luckow B, Horster M (1998) CFTR mRNA and its truncated splice variant (TRN-CFTR) are differentially expressed during collecting duct ontogeny. FEBS Lett 423:362–366

    Article  CAS  PubMed  Google Scholar 

  • Inagaki N, Gonoi T, Clement JP, Namba N, Inazawa J, Gonzalez G, Aguilar-Bryan L, Seino S, Bryan J (1995a) Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor. Science 270:1166–1170

    Article  CAS  PubMed  Google Scholar 

  • Inagaki N, Inazawa J, Seino S (1995b) cDNA sequence, gene structure, and chromosomal localization of the human ATP-sensitive potassium channel, uKATP-1, gene (KCNJ8). Genomics 30:102–104

    Article  CAS  PubMed  Google Scholar 

  • Inagaki N, Tsuura Y, Namba N, Masuda K, Gonoi T, Horie M, Seino Y, Mizuta M, Seino S (1995c) Cloning and functional characterization of a novel ATP-sensitive potassium channel ubiquitously expressed in rat tissues, including pancreatic islets, pituitary, skeletal muscle, and heart. J Biol Chem 270:5691–5694

    Article  CAS  PubMed  Google Scholar 

  • Inglis SK, Collett A, McAlroy HL, Wilson SM, Olver RE (1999) Effect of luminal nucleotides on Cl– secretion and Na+ absorption in distal bronchi. Pflugers Arch 438:621–627

    Article  CAS  PubMed  Google Scholar 

  • Iwase N, Sasaki T, Shimura S, Yamamoto M, Suzuki S, Shirato K (1997) ATP-induced Cl– secretion with suppressed Na+ absorption in rabbit tracheal epithelium. Respir Physiol 107:173–180

    Article  CAS  PubMed  Google Scholar 

  • Jouret F, Devuyst O (2008) CFTR and defective endocytosis: new insights in the renal phenotype of cystic fibrosis. Pflugers Arch 457:1227–1236

    Article  PubMed  Google Scholar 

  • Jouret F, Bernard A, Hermans C, Dom G, Terryn S, Leal T, Lebecque P, Cassiman JJ, Scholte BJ, de Jonge HR, Courtoy PJ, Devuyst O (2007) Cystic fibrosis is associated with a defect in apical receptor-mediated endocytosis in mouse and human kidney. J Am Soc Nephrol 18:707–718

    Article  CAS  PubMed  Google Scholar 

  • Konstas AA, Koch JP, Korbmacher C (2003) cAMP-dependent activation of CFTR inhibits the epithelial sodium channel (ENaC) without affecting its surface expression. Pflugers Arch 445:513–521

    CAS  PubMed  Google Scholar 

  • Kunzelmann K (2003) ENaC is inhibited by an increase in the intracellular Cl(–) concentration mediated through activation of Cl(–) channels. Pflugers Arch 445:504–512

    CAS  PubMed  Google Scholar 

  • Kunzelmann K, Schreiber R (1999) CFTR, a regulator of channels. J Membr Biol 168:1–8

    Article  CAS  PubMed  Google Scholar 

  • Kunzelmann K, Schreiber R, Nitschke R, Mall M (2000) Control of epithelial Na+ conductance by the cystic fibrosis transmembrane conductance regulator. Pflugers Arch 440:193–201

    CAS  PubMed  Google Scholar 

  • Kunzelmann K, Schreiber R, Boucherot A (2001) Mechanisms of the inhibition of epithelial Na(+) channels by CFTR and purinergic stimulation. Kidney Int 60:455–461

    Article  CAS  PubMed  Google Scholar 

  • Lassance-Soares RM, Cheng J, Krasnov K, Cebotaru L, Cutting GR, Souza-Menezes J, Morales MM, Guggino WB (2010) The hypertonic environment differentially regulates wild-type CFTR and TNR-CFTR chloride channels. Cell Physiol Biochem 26:577–586

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Li C, Naren AP (2010) CFTR chloride channel in the apical compartments: spatiotemporal coupling to its interacting partners. Integr Biol (Camb) 2:161–177

    Article  Google Scholar 

  • Lu M, Dong K, Egan ME, Giebisch GH, Boulpaep EL, Hebert SC (2010) Mouse cystic fibrosis transmembrane conductance regulator forms cAMP-PKA-regulated apical chloride channels in cortical collecting duct. Proc Natl Acad Sci USA 107:6082–6087

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mall M, Bleich M, Greger R, Schreiber R, Kunzelmann K (1998) The amiloride-inhibitable Na+ conductance is reduced by the cystic fibrosis transmembrane conductance regulator in normal but not in cystic fibrosis airways. J Clin Invest 102:15–21

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • McCoy DE, Taylor AL, Kudlow BA, Karlson K, Slattery MJ, Schwiebert LM, Schwiebert EM, Stanton BA (1999) Nucleotides regulate NaCl transport in mIMCD-K2 cells via P2X and P2Y purinergic receptors. Am J Physiol 277:F552–F559

    CAS  PubMed  Google Scholar 

  • McNicholas CM, Guggino WB, Schwiebert EM, Hebert SC, Giebisch G, Egan ME (1996a) Sensitivity of a renal K+ channel (ROMK2) to the inhibitory sulfonylurea compound glibenclamide is enhanced by coexpression with the ATP-binding cassette transporter cystic fibrosis transmembrane regulator. Proc Natl Acad Sci USA 93:8083–8088

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • McNicholas CM, Yang Y, Giebisch G, Hebert SC (1996b) Molecular site for nucleotide binding on an ATP-sensitive renal K+ channel (ROMK2). Am J Physiol 271:F275–F285

    CAS  PubMed  Google Scholar 

  • McNicholas CM, Nason MW Jr, Guggino WB, Schwiebert EM, Hebert SC, Giebisch G, Egan ME (1997) A functional CFTR-NBF1 is required for ROMK2-CFTR interaction. Am J Physiol 273:F843–F848

    CAS  PubMed  Google Scholar 

  • Morales MM, Carroll TP, Morita T, Schwiebert EM, Devuyst O, Wilson PD, Lopes AG, Stanton BA, Dietz HC, Cutting GR, Guggino WB (1996) Both the wild type and a functional isoform of CFTR are expressed in kidney. Am J Physiol 270:F1038–F1048

    CAS  PubMed  Google Scholar 

  • Morales MM, Capella MA, Lopes AG (1999) Structure and function of the cystic fibrosis transmembrane conductance regulator. Braz J Med Biol Res 32:1021–1028

    Article  CAS  PubMed  Google Scholar 

  • Morales MM, Falkenstein D, Lopes AG (2000) The cystic fibrosis transmembrane regulator (CFTR) in the kidney. An Acad Bras Cienc 72:399–406

    Article  CAS  PubMed  Google Scholar 

  • Morales MM, Nascimento DS, Capella MA, Lopes AG, Guggino WB (2001) Arginine vasopressin regulates CFTR and ClC-2 mRNA expression in rat kidney cortex and medulla. Pflugers Arch 443:202–211

    Article  CAS  PubMed  Google Scholar 

  • Morris RG, Schafer JA (2002) cAMP increases density of ENaC subunits in the apical membrane of MDCK cells in direct proportion to amiloride-sensitive Na(+) transport. J Gen Physiol 120:71–85

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mosser J, Douar AM, Sarde CO, Kioschis P, Feil R, Moser H, Poustka AM, Mandel JL, Aubourg P (1993) Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature 361:726–730

    Article  CAS  PubMed  Google Scholar 

  • Planells-Cases R, Jentsch TJ (2009) Chloride channelopathies. Biochim Biophys Acta 1792:173–189

    Article  CAS  PubMed  Google Scholar 

  • Riordan JR (1993) The cystic fibrosis transmembrane conductance regulator. Annu Rev Physiol 55:609–630

    Article  CAS  PubMed  Google Scholar 

  • Rogan MP, Stoltz DA, Hornick DB (2011) Cystic fibrosis transmembrane conductance regulator intracellular processing, trafficking, and opportunities for mutation-specific treatment. Chest 139:1480–1490

    Article  CAS  PubMed  Google Scholar 

  • Ruknudin A, Schulze DH, Sullivan SK, Lederer WJ, Welling PA (1998) Novel subunit composition of a renal epithelial KATP channel. J Biol Chem 273:14165–14171

    Article  CAS  PubMed  Google Scholar 

  • Schwiebert EM, Kishore BK (2001) Extracellular nucleotide signaling along the renal epithelium. Am J Physiol Renal Physiol 280:F945–F963

    CAS  PubMed  Google Scholar 

  • Schwiebert EM, Morales MM, Devidas S, Egan ME, Guggino WB (1998) Chloride channel and chloride conductance regulator domains of CFTR, the cystic fibrosis transmembrane conductance regulator. Proc Natl Acad Sci USA 95:2674–2679

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Schwiebert EM, Benos DJ, Egan ME, Stutts MJ, Guggino WB (1999) CFTR is a conductance regulator as well as a chloride channel. Physiol Rev 79:S145–S166

    CAS  PubMed  Google Scholar 

  • Souza-Menezes J, Morales MM, Tukaye DN, Guggino SE, Guggino WB (2007) Absence of ClC5 in knockout mice leads to glycosuria, impaired renal glucose handling and low proximal tubule GLUT2 protein expression. Cell Physiol Biochem 20:455–464

    Article  CAS  PubMed  Google Scholar 

  • Souza-Menezes J, Tukaye DN, Novaira HJ, Guggino WB, Morales MM (2008) Small nuclear RNAs U11 and U12 modulate expression of TNR-CFTR mRNA in mammalian kidneys. Cell Physiol Biochem 22:93–100

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Stratford FL, Ramjeesingh M, Cheung JC, Huan LJ, Bear CE (2007) The Walker B motif of the second nucleotide-binding domain (NBD2) of CFTR plays a key role in ATPase activity by the NBD1-NBD2 heterodimer. Biochem J 401:581–586

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Stutts MJ, Canessa CM, Olsen JC, Hamrick M, Cohn JA, Rossier BC, Boucher RC (1995) CFTR as a cAMP-dependent regulator of sodium channels. Science 269:847–850

    Article  CAS  PubMed  Google Scholar 

  • Sugita M, Yue Y, Foskett JK (1998) CFTR Cl– channel and CFTR-associated ATP channel: distinct pores regulated by common gates. EMBO J 17:898–908

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Taal MW, Chertow GM, Marsden PA, Skorecki K, Yu ASL, Brenner BM (eds) (2012) Brenner & Rector's the kidney, 9th edn. Elsevier Saunders, Philadelphia

    Google Scholar 

  • Valle D, Gartner J (1993) Human genetics. Penetrating the peroxisome. Nature 361:682–683

    Article  CAS  PubMed  Google Scholar 

  • Vergani P, Lockless SW, Nairn AC, Gadsby DC (2005) CFTR channel opening by ATP-driven tight dimerization of its nucleotide-binding domains. Nature 433:876–880

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wang W (1999) Regulation of the ROMK channel: interaction of the ROMK with associate proteins. Am J Physiol 277:F826–F831

    CAS  PubMed  Google Scholar 

  • Wang W, Hebert SC, Giebisch G (1997) Renal K+ channels: structure and function. Annu Rev Physiol 59:413–436

    Article  CAS  PubMed  Google Scholar 

  • Xie Y, Schafer JA (2004) Inhibition of ENaC by intracellular Cl– in an MDCK clone with high ENaC expression. Am J Physiol Renal Physiol 287:F722–F731

    Article  CAS  PubMed  Google Scholar 

  • Xie Y, Schafer JA (2008) Endogenous ATP release inhibits electrogenic Na(+) absorption and stimulates Cl(–) secretion in MDCK cells. Purinergic Signal 4:125–137

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yunos NM, Bellomo R, Story D, Kellum J (2010) Bench-to-bedside review: chloride in critical illness. Crit Care 14:226

    Article  PubMed Central  PubMed  Google Scholar 

  • Zaitseva J, Jenewein S, Jumpertz T, Holland IB, Schmitt L (2005) H662 is the linchpin of ATP hydrolysis in the nucleotide-binding domain of the ABC transporter HlyB. EMBO J 24:1901–1910

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

This study was supported by FAPERJ, CNPq, CAPES, and INCT.

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Conflict of Interest

Jackson Souza-Menezes, Geórgia da Silva Feltran and Marcelo M. Morales declare that they have no conflict of interest.

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

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  1. Laboratório Integrado de Ciências Morfofuncionais, Núcleo em Ecologia e Desenvolvimento Sócio-Ambiental, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Av. São José do Barreto, 764, Barreto, Macaé, 27965-045, RJ, Brazil

    Jackson Souza-Menezes & Geórgia da Silva Feltran

  2. Laboratório de Fisiologia Celular e Molecular, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil

    Jackson Souza-Menezes & Marcelo M. Morales

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  1. Jackson Souza-Menezes
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Souza-Menezes, J., da Silva Feltran, G. & Morales, M.M. CFTR and TNR-CFTR expression and function in the kidney. Biophys Rev 6, 227–236 (2014). https://doi.org/10.1007/s12551-014-0140-8

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