Skip to main content

Advertisement

Log in

Receptor-mediated endocytosis in renal proximal tubule

  • Ion Channels, Receptors and Transporters
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Proteins filtered in renal glomeruli are removed from the tubular fluid by endocytosis in the proximal tubule mediated by the two receptors megalin and cubilin. After endocytic uptake, the proteins are transferred to lysosomes for degradation, while the receptors are returned to the apical cell membrane by receptor recycling in dense apical tubules. In the renal proximal tubule, there is no significant transcellular transport of protein. The reabsorptive process is extremely efficient as evidenced by the virtual protein free urine in humans. The two receptors bind a variety of ligands. The process serves not only to remove the proteins from the ultrafiltrate but also to conserve a variety of essential substances such as vitamins and trace elements carried by plasma proteins. The endocytic apparatus is highly developed in the proximal tubule demonstrating the high capacity of the cells; however, under certain circumstances like diseases affecting the glomeruli, the system is overloaded resulting in proteinuria.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Ahuja R, Yammani R, Bauer JA, Kalra S, Seetharam S, Seetharam B (2008) Interactions of cubilin with megalin and the product of the amnionless gene (AMN): effect on its stability. Biochem J 410:301–308

    Article  PubMed  CAS  Google Scholar 

  2. Ambjorn M, Asmussen JW, Lindstam M, Gotfryd K, Jacobsen C, Kiselyov VV, Moestrup SK, Penkowa M, Bock E, Berezin V (2008) Metallothionein and a peptide modeled after metallothionein, EmtinB, induce neuronal differentiation and survival through binding to receptors of the low-density lipoprotein receptor family. J Neurochem 104:21–37

    PubMed  Google Scholar 

  3. Aminoff M, Carter JE, Chadwick RB, Johnson C, Grasbeck R, Abdelaal MA, Broch H, Jenner LB, Verroust PJ, Moestrup SK, de la Chapelle A, Krahe R (1999) Mutations in CUBN, encoding the intrinsic factor–vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1. Nat Genet 21:309–313

    Article  PubMed  CAS  Google Scholar 

  4. Assemat E, Chatelet F, Chandellier J, Commo F, Cases O, Verroust P, Kozyraki R (2005) Overlapping expression patterns of the multiligand endocytic receptors cubilin and megalin in the CNS, sensory organs and developing epithelia of the rodent embryo. Gene Expr Patterns 6:69–78

    Article  PubMed  CAS  Google Scholar 

  5. Assemat E, Vinot S, Gofflot F, Linsel-Nitschke P, Illien F, Chatelet F, Verroust P, Louvet-Vallee S, Rinninger F, Kozyraki R (2005) Expression and role of cubilin in the internalization of nutrients during the peri-implantation development of the rodent embryo. Biol Reprod 72:1079–1086

    Article  PubMed  CAS  Google Scholar 

  6. Bieri S, Atkins AR, Lee HT, Winzor DJ, Smith R, Kroon PA (1998) Folding, calcium binding, and structural characterization of a concatemer of the first and second ligand-binding modules of the low-density lipoprotein receptor. Biochemistry 37:10994–11002

    Article  PubMed  CAS  Google Scholar 

  7. Birn H, Christensen EI (2006) Renal albumin absorption in physiology and pathology. Kidney Int 69:440–449

    Article  PubMed  CAS  Google Scholar 

  8. Birn H, Fyfe JC, Jacobsen C, Mounier F, Verroust PJ, Orskov H, Willnow TE, Moestrup SK, Christensen EI (2000) Cubilin is an albumin binding protein important for renal tubular albumin reabsorption. J Clin Invest 105:1353–1361

    Article  PubMed  CAS  Google Scholar 

  9. Birn H, Nexo E, Christensen EI, Nielsen R (2003) Diversity in rat tissue accumulation of vitamin B12 supports a distinct role for the kidney in vitamin B12 homeostasis. Nephrol Dial Transplant 18:1095–1100

    Article  PubMed  CAS  Google Scholar 

  10. Birn H, Verroust PJ, Nexø E, Hager H, Jacobsen C, Christensen EI, Moestrup SK (1997) Characterization of an epithelial approximately 460-kDa protein that facilitates endocytosis of intrinsic factor–vitamin B12 and binds receptor-associated protein. J Biol Chem 272:26497–26504

    Article  PubMed  CAS  Google Scholar 

  11. Birn H, Vorum H, Verroust PJ, Moestrup SK, Christensen EI (2000) Receptor-associated protein is important for normal processing of megalin in kidney proximal tubules. J Am Soc Nephrol 11:191–202

    PubMed  CAS  Google Scholar 

  12. Bork P, Beckmann G (1993) The CUB domain. A widespread module in developmentally regulated proteins. J Mol Biol 231:539–545

    Article  PubMed  CAS  Google Scholar 

  13. Bu G, Geuze HJ, Strous GJ, Schwartz AL (1995) 39 kDa receptor-associated protein is an ER resident protein and molecular chaperone for LDL receptor-related protein. EMBO J 14:2269–2280

    PubMed  CAS  Google Scholar 

  14. Bu G, Rennke S (1996) Receptor-associated protein is a folding chaperone for low density lipoprotein receptor-related protein. J Biol Chem 271:22218–22224

    Article  PubMed  CAS  Google Scholar 

  15. Chowdhary BP, Lundgren S, Johansson M, Hjalm G, Åkerström G, Gustavsson I, Rask L (1995) In situ hybridization mapping of a 500-kDa calcium-sensing protein gene (LRP2) to human chromosome region 2q31–>q32.1 and porcine chromosome region 15q22–>q24. Cytogenet Cell Genet 71:120–123

    Article  PubMed  CAS  Google Scholar 

  16. Christensen EI (1982) Rapid membrane recycling in renal proximal tubule cells. Eur J Cell Biol 29:43–49

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  18. Christensen EI, Birn H, Rippe B, Maunsbach AB (2007) Controversies in nephrology: renal albumin handling, facts, and artifacts!. Kidney Int 72:1192–1194

    Article  PubMed  CAS  Google Scholar 

  19. Christensen EI, Birn H, Verroust P, Moestrup SK (1998) Membrane receptors for endocytosis in the renal proximal tubule. Int Rev Cytol 180:237–284

    Article  PubMed  CAS  Google Scholar 

  20. Christensen EI, Moskaug JO, Vorum H, Jacobsen C, Gundersen TE, Nykjær A, Blomhoff R, Willnow TE, Moestrup SK (1999) Evidence for an essential role of megalin in transepithelial transport of retinol. J Am Soc Nephrol 10:685–695

    PubMed  CAS  Google Scholar 

  21. Christensen EI, Nielsen R (2007) Role of megalin and cubilin in renal physiology and pathophysiology. Rev Physiol Biochem Pharmacol 158:1–22

    Article  PubMed  CAS  Google Scholar 

  22. Christensen EI, Raciti D, Reggiani L, Verroust PJ, Brandli AW (2008) Gene expression analysis defines the proximal tubule as the compartment for endocytic receptor-mediated uptake in the Xenopus pronephric kidney. Pflugers Arch 456:1163–1176

    Article  PubMed  CAS  Google Scholar 

  23. Christensen EI, Verroust PJ (2006) Expression of megalin and cubilin in rat glomerular podocytes. J Am Soc Neph 17:541A

    Google Scholar 

  24. Christensen EI, Zhou Q, Sorensen SS, Rasmussen AK, Jacobsen C, Feldt-Rasmussen U, Nielsen R (2007) Distribution of alpha-galactosidase A in normal human kidney and renal accumulation and distribution of recombinant alpha-galactosidase A in Fabry mice. J Am Soc Nephrol 18:698–706

    Article  PubMed  CAS  Google Scholar 

  25. Comper WD, Hilliard LM, Nikolic-Paterson DJ, Russo LM (2008) Disease-dependent mechanisms of albuminuria. Am J Physiol Renal Physiol 295:F1589–F1600

    Article  PubMed  CAS  Google Scholar 

  26. Coudroy G, Gburek J, Kozyraki R, Madsen M, Trugnan G, Moestrup SK, Verroust PJ, Maurice M (2005) Contribution of cubilin and amnionless to processing and membrane targeting of cubilin–amnionless complex. J Am Soc Nephrol 16:2330–2337

    Article  PubMed  CAS  Google Scholar 

  27. Cui S, Verroust PJ, Moestrup SK, Christensen EI (1996) Megalin/gp330 mediates uptake of albumin in renal proximal tubule. Am J Physiol 271:F900–F907

    PubMed  CAS  Google Scholar 

  28. Davis CG, Goldstein JL, Sudhof TC, Anderson RG, Russell DW, Brown MS (1987) Acid-dependent ligand dissociation and recycling of LDL receptor mediated by growth factor homology region. Nature 326:760–765

    Article  PubMed  CAS  Google Scholar 

  29. Fass D, Blacklow S, Kim PS, Berger JM (1997) Molecular basis of familial hypercholesterolaemia from structure of LDL receptor module. Nature 388:691–693

    Article  PubMed  CAS  Google Scholar 

  30. Fleming CE, Mar FM, Franquinho F, Saraiva MJ, Sousa MM (2009) Transthyretin internalization by sensory neurons is megalin mediated and necessary for its neuritogenic activity. J Neurosci 29:3220–3232

    Article  PubMed  CAS  Google Scholar 

  31. Fyfe JC, Giger U, Hall CA, Jezyk PF, Klumpp SA, Levine JS, Patterson DF (1991) Inherited selective intestinal cobalamin malabsorption and cobalamin deficiency in dogs. Pediatr Res 29:24–31

    Article  PubMed  CAS  Google Scholar 

  32. Fyfe JC, Madsen M, Hojrup P, Christensen EI, Tanner SM, de la Chapelle A, He Q, Moestrup SK (2004) The functional cobalamin (vitamin B12)–intrinsic factor receptor is a novel complex of cubilin and amnionless. Blood 103:1573–1579

    Article  PubMed  CAS  Google Scholar 

  33. Fyfe JC, Ramanujam KS, Ramaswamy K, Patterson DF, Seetharam B (1991) Defective brush-border expression of intrinsic factor–cobalamin receptor in canine inherited intestinal cobalamin malabsorption. J Biol Chem 266:4489–4494

    PubMed  CAS  Google Scholar 

  34. Gekle M (2007) Renal albumin handling: a look at the dark side of the filter. Kidney Int 71:479–481

    Article  PubMed  CAS  Google Scholar 

  35. Gotthardt M, Trommsdorff M, Nevitt MF, Shelton J, Richardson JA, Stockinger W, Nimpf J, Herz J (2000) Interactions of the low density lipoprotein receptor gene family with cytosolic adaptor and scaffold proteins suggest diverse biological functions in cellular communication and signal transduction. J Biol Chem 275:25616–25624

    Article  PubMed  CAS  Google Scholar 

  36. He Q, Madsen M, Kilkenney A, Gregory B, Christensen EI, Vorum H, Hojrup P, Schaffer AA, Kirkness EF, Tanner SM, de la Chapelle A, Giger U, Moestrup SK, Fyfe JC (2005) Amnionless function is required for cubilin brush-border expression and intrinsic factor–cobalamin (vitamin B12) absorption in vivo. Blood 106:1447–1453

    Article  PubMed  CAS  Google Scholar 

  37. Hjälm G, Murray E, Crumley G, Harazim W, Lundgren S, Onyango I, Ek B, Larsson M, Juhlin C, Hellman P, Davis H, Åkerström G, Rask L, Morse B (1996) Cloning and sequencing of human gp330, a Ca(2+)-binding receptor with potential intracellular signaling properties. Eur J Biochem 239:132–137

    Article  PubMed  Google Scholar 

  38. Hosaka K, Takeda T, Iino N, Hosojima M, Sato H, Kaseda R, Yamamoto K, Kobayashi A, Gejyo F, Saito A (2009) Megalin and nonmuscle myosin heavy chain IIA interact with the adaptor protein Disabled-2 in proximal tubule cells. Kidney Int (in press)

  39. Kalantry S, Manning S, Haub O, Tomihara-Newberger C, Lee HG, Fangman J, Disteche CM, Manova K, Lacy E (2001) The amnionless gene, essential for mouse gastrulation, encodes a visceral–endoderm-specific protein with an extracellular cysteine-rich domain. Nat Genet 27:412–416

    Article  PubMed  CAS  Google Scholar 

  40. Kantarci S, Al-Gazali L, Hill RS, Donnai D, Black GC, Bieth E, Chassaing N, Lacombe D, Devriendt K, Teebi A, Loscertales M, Robson C, Liu T, Maclaughlin DT, Noonan KM, Russell MK, Walsh CA, Donahoe PK, Pober BR (2007) Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai–Barrow and facio-oculo-acoustico-renal syndromes. Nat Genet 39:957–959

    Article  PubMed  CAS  Google Scholar 

  41. Kerjaschki D, Farquhar MG (1982) The pathogenic antigen of Heymann nephritis is a membrane glycoprotein of the renal proximal tubule brush border. Proc Natl Acad Sci U S A 79:5557–5561

    Article  PubMed  CAS  Google Scholar 

  42. Kerjaschki D, Farquhar MG (1983) Immunocytochemical localization of the Heymann nephritis antigen (GP330) in glomerular epithelial cells of normal Lewis rats. J Exp Med 157:667–686

    Article  PubMed  CAS  Google Scholar 

  43. Keyel PA, Thieman JR, Roth R, Erkan E, Everett ET, Watkins SC, Heuser JE, Traub LM (2008) The AP-2 adaptor beta2 appendage scaffolds alternate cargo endocytosis. Mol Biol Cell 19:5309–5326

    Article  PubMed  CAS  Google Scholar 

  44. Kozyraki R, Fyfe J, Kristiansen M, Gerdes C, Jacobsen C, Cui S, Christensen EI, Aminoff M, de la Chapelle A, Krahe R, Verroust PJ, Moestrup SK (1999) The intrinsic factor–vitamin B12 receptor, cubilin, is a high-affinity apolipoprotein A-I receptor facilitating endocytosis of high-density lipoprotein. Nat Med 5:656–661

    Article  PubMed  CAS  Google Scholar 

  45. Kozyraki R, Fyfe J, Verroust PJ, Jacobsen C, Dautry-Varsat A, Gburek J, Willnow TE, Christensen EI, Moestrup SK (2001) Megalin-dependent cubilin-mediated endocytosis is a major pathway for the apical uptake of transferrin in polarized epithelia. Proc Natl Acad Sci U S A 98:12491–12496

    Article  PubMed  CAS  Google Scholar 

  46. Kozyraki R, Kristiansen M, Silahtaroglu A, Hansen C, Jacobsen C, Tommerup N, Verroust PJ, Moestrup SK (1998) The human intrinsic factor–vitamin B12 receptor, cubilin: molecular characterization and chromosomal mapping of the gene to 10p within the autosomal recessive megaloblastic anemia (MGA1) region. Blood 91:3593–3600

    PubMed  CAS  Google Scholar 

  47. Kristiansen M, Kozyraki R, Jacobsen C, Nexø E, Verroust PJ, Moestrup SK (1999) Molecular dissection of the intrinsic factor–vitamin B12 receptor, cubilin, discloses regions important for membrane association and ligand binding. J Biol Chem 274:20540–20544

    Article  PubMed  CAS  Google Scholar 

  48. Larrain J, Bachiller D, Lu B, Agius E, Piccolo S, De Robertis EM (2000) BMP-binding modules in chordin: a model for signalling regulation in the extracellular space. Development 127:821–830

    PubMed  CAS  Google Scholar 

  49. Larsson M, Hjalm G, Sakwe AM, Engstrom A, Hoglund AS, Larsson E, Robinson RC, Sundberg C, Rask L (2003) Selective interaction of megalin with postsynaptic density-95 (PSD-95)-like membrane-associated guanylate kinase (MAGUK) proteins. Biochem J 373:381–391

    Article  PubMed  CAS  Google Scholar 

  50. Maunsbach AB (1966) Absorption of I125-labeled homologous albumin by rat kidney proximal tubule cells. A study of microperfused single proximal tubules by electron microscopic autoradiography and histochemistry. J Ultrastruct Res 15:197–241

    Article  PubMed  CAS  Google Scholar 

  51. Moestrup SK, Birn H, Fischer PB, Petersen CM, Verroust PJ, Sim RB, Christensen EI, Nexø E (1996) Megalin-mediated endocytosis of transcobalamin–vitamin-B12 complexes suggests a role of the receptor in vitamin-B12 homeostasis. Proc Natl Acad Sci U S A 93:8612–8617

    Article  PubMed  CAS  Google Scholar 

  52. Moestrup SK, Kozyraki R, Kristiansen M, Kaysen JH, Rasmussen HH, Brault D, Pontillon F, Goda FO, Christensen EI, Hammond TG, Verroust PJ (1998) The intrinsic factor–vitamin B12 receptor and target of teratogenic antibodies is a megalin-binding peripheral membrane protein with homology to developmental proteins. J Biol Chem 273:5235–5242

    Article  PubMed  CAS  Google Scholar 

  53. Morris SM, Arden SD, Roberts RC, Kendrick-Jones J, Cooper JA, Luzio JP, Buss F (2002) Myosin VI binds to and localises with Dab2, potentially linking receptor-mediated endocytosis and the actin cytoskeleton. Traffic 3:331–341

    Article  PubMed  CAS  Google Scholar 

  54. Morris SM, Tallquist MD, Rock CO, Cooper JA (2002) Dual roles for the Dab2 adaptor protein in embryonic development and kidney transport. EMBO J 21:1555–1564

    Article  PubMed  CAS  Google Scholar 

  55. Motoyoshi Y, Matsusaka T, Saito A, Pastan I, Willnow TE, Mizutani S, Ichikawa I (2008) Megalin contributes to the early injury of proximal tubule cells during nonselective proteinuria. Kidney Int 74:1262–1269

    Article  PubMed  CAS  Google Scholar 

  56. Nagai J, Christensen EI, Morris SM, Willnow TE, Cooper JA, Nielsen R (2005) Mutually dependent localization of megalin and Dab2 in the renal proximal tubule. Am J Physiol Renal Physiol 289:F569–F576

    Article  PubMed  CAS  Google Scholar 

  57. Nagai M, Meerloo T, Takeda T, Farquhar MG (2003) The adaptor protein ARH escorts megalin to and through endosomes. Mol Biol Cell 14:4984–4996

    Article  PubMed  CAS  Google Scholar 

  58. Nielsen R, Courtoy PJ, Jacobsen C, Dom G, Lima WR, Jadot M, Willnow TE, Devuyst O, Christensen EI (2007) Endocytosis provides a major alternative pathway for lysosomal biogenesis in kidney proximal tubular cells. Proc Natl Acad Sci U S A 104:5407–5412

    Article  PubMed  CAS  Google Scholar 

  59. Nykjær A, Dragun D, Walther D, Vorum H, Jacobsen C, Herz J, Melsen F, Christensen EI, Willnow TE (1999) An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3. Cell 96:507–515

    Article  PubMed  Google Scholar 

  60. Nykjaer A, Fyfe JC, Kozyraki R, Leheste JR, Jacobsen C, Nielsen MS, Verroust PJ, Aminoff M, de la Chapelle A, Moestrup SK, Ray R, Gliemann J, Willnow TE, Christensen EI (2001) Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D(3). Proc Natl Acad Sci U S A 98:13895–13900

    Article  PubMed  CAS  Google Scholar 

  61. Oleinikov AV, Zhao J, Makker SP (2000) Cytosolic adaptor protein Dab2 is an intracellular ligand of endocytic receptor gp600/megalin. Biochem J 347:613–621

    Article  PubMed  CAS  Google Scholar 

  62. Orlando RA, Exner M, Czekay RP, Yamazaki H, Saito A, Ullrich R, Kerjaschki D, Farquhar MG (1997) Identification of the second cluster of ligand-binding repeats in megalin as a site for receptor-ligand interactions. Proc Natl Acad Sci U S A 94:2368–2373

    Article  PubMed  CAS  Google Scholar 

  63. Park CH, Maack T (1984) Albumin absorption and catabolism by isolated perfused proximal convoluted tubules of the rabbit. J Clin Invest 73:767–777

    Article  PubMed  CAS  Google Scholar 

  64. Petersen HH, Hilpert J, Militz D, Zandler V, Jacobsen C, Roebroek AJ, Willnow TE (2003) Functional interaction of megalin with the megalinbinding protein (MegBP), a novel tetratrico peptide repeat-containing adaptor molecule. J Cell Sci 116:453–461

    Article  PubMed  CAS  Google Scholar 

  65. Peti-Peterdi J (2009) Independent two-photon measurements of albumin GSC give low values. Am J Physiol Renal Physiol 296:1255–1257

    Google Scholar 

  66. Raychowdhury R, Niles JL, McCluskey RT, Smith JA (1989) Autoimmune target in Heymann nephritis is a glycoprotein with homology to the LDL receptor. Science 244:1163–1165

    Article  PubMed  CAS  Google Scholar 

  67. Remuzzi A, Sangalli F, Fassi A, Remuzzi G (2007) Albumin concentration in the Bowman's capsule: multiphoton microscopy vs micropuncture technique. Kidney Int 72:1410–1411

    Article  PubMed  CAS  Google Scholar 

  68. Russell DW, Brown MS, Goldstein JL (1989) Different combinations of cysteine-rich repeats mediate binding of low density lipoprotein receptor to two different proteins. J Biol Chem 264:21682–21688

    PubMed  CAS  Google Scholar 

  69. Russo LM, Sandoval RM, Campos SB, Molitoris BA, Comper WD, Brown D (2009) Impaired tubular uptake explains albuminuria in early diabetic nephropathy. J Am Soc Nephrol 20:489–494

    Article  PubMed  Google Scholar 

  70. Russo LM, Sandoval RM, McKee M, Osicka TM, Collins AB, Brown D, Molitoris BA, Comper WD (2007) The normal kidney filters nephrotic levels of albumin retrieved by proximal tubule cells: retrieval is disrupted in nephrotic states. Kidney Int 71:504–513

    Article  PubMed  CAS  Google Scholar 

  71. Saito A, Pietromonaco S, Loo AK, Farquhar MG (1994) Complete cloning and sequencing of rat gp330/"megalin," a distinctive member of the low density lipoprotein receptor gene family. Proc Natl Acad Sci U S A 91:9725–9729

    Article  PubMed  CAS  Google Scholar 

  72. Schmid EM, Ford MG, Burtey A, Praefcke GJ, Peak-Chew SY, Mills IG, Benmerah A, McMahon HT (2006) Role of the AP2 beta-appendage hub in recruiting partners for clathrin-coated vesicle assembly. PLoS Biol 4:e262

    Article  PubMed  CAS  Google Scholar 

  73. Seetharam B, Christensen EI, Moestrup SK, Hammond TG, Verroust PJ (1997) Identification of rat yolk sac target protein of teratogenic antibodies, gp280, as intrinsic factor-cobalamin receptor. J Clin Invest 99:2317–2322

    Article  PubMed  CAS  Google Scholar 

  74. Seetharam B, Levine JS, Ramasamy M, Alpers DH (1988) Purification, properties, and immunochemical localization of a receptor for intrinsic factor–cobalamin complex in the rat kidney. J Biol Chem 263:4443–4449

    PubMed  CAS  Google Scholar 

  75. Smith BT, Mussell JC, Fleming PA, Barth JL, Spyropoulos DD, Cooley MA, Drake CJ, Argraves WS (2006) Targeted disruption of cubilin reveals essential developmental roles in the structure and function of endoderm and in somite formation. BMC Dev Biol 6:30

    Article  PubMed  CAS  Google Scholar 

  76. Strope S, Rivi R, Metzger T, Manova K, Lacy E (2004) Mouse amnionless, which is required for primitive streak assembly, mediates cell-surface localization and endocytic function of cubilin on visceral endoderm and kidney proximal tubules. Development 131:4787–4795

    Article  PubMed  CAS  Google Scholar 

  77. Takeda T, Yamazaki H, Farquhar MG (2003) Identification of an apical sorting determinant in the cytoplasmic tail of megalin. Am J Physiol Cell Physiol 284:C1105–C1113

    PubMed  CAS  Google Scholar 

  78. Tanner GA (2009) Glomerular sieving coefficient of serum albumin in the rat: a two-photon microscopy study. Am J Physiol Renal Physiol 296:1258–1265

    Google Scholar 

  79. Tanner SM, Aminoff M, Wright FA, Liyanarachchi S, Kuronen M, Saarinen A, Massika O, Mandel H, Broch H, de la Chapelle A (2003) Amnionless, essential for mouse gastrulation, is mutated in recessive hereditary megaloblastic anemia. Nat Genet 33:426–429

    Article  PubMed  CAS  Google Scholar 

  80. Tanner SM, Li Z, Bisson R, Acar C, Oner C, Oner R, Cetin M, Abdelaal MA, Ismail EA, Lissens W, Krahe R, Broch H, Grasbeck R, de la Chapelle A (2004) Genetically heterogeneous selective intestinal malabsorption of vitamin B12: founder effects, consanguinity, and high clinical awareness explain aggregations in Scandinavia and the Middle East. Hum Mutat 23:327–333

    Article  PubMed  CAS  Google Scholar 

  81. Tauris J, Christensen EI, Nykjaer A, Jacobsen C, Petersen CM, Ovesen T (2009) Cubilin and megalin co-localize in the neonatal inner ear. Audiol Neurootol 14:267–278

    Article  PubMed  CAS  Google Scholar 

  82. Willnow TE (1998) Receptor-associated protein (RAP): a specialized chaperone for endocytic receptors. Biol Chem 379:1025–1031

    PubMed  CAS  Google Scholar 

  83. Willnow TE, Armstrong SA, Hammer RE, Herz J (1995) Functional expression of low density lipoprotein receptor- related protein is controlled by receptor-associated protein in vivo. Proc Natl Acad Sci U S A 92:4537–4541

    Article  PubMed  CAS  Google Scholar 

  84. Willnow TE, Hilpert J, Armstrong SA, Rohlmann A, Hammer RE, Burns DK, Herz J (1996) Defective forebrain development in mice lacking gp330/megalin. Proc Natl Acad Sci U S A 93:8460–8464

    Article  PubMed  CAS  Google Scholar 

  85. Willnow TE, Rohlmann A, Horton J, Otani H, Braun JR, Hammer RE, Herz J (1996) RAP, a specialized chaperone, prevents ligand-induced ER retention and degradation of LDL receptor-related endocytic receptors. EMBO J 15:2632–2639

    PubMed  CAS  Google Scholar 

  86. Wolf CA, Dancea F, Shi M, Bade-Noskova V, Ruterjans H, Kerjaschki D, Lucke C (2007) Solution structure of the twelfth cysteine-rich ligand-binding repeat in rat megalin. J Biomol NMR 37:321–328

    Article  PubMed  CAS  Google Scholar 

  87. Xu D, Kozyraki R, Newman TC, Fyfe JC (1999) Genetic evidence of an accessory activity required specifically for cubilin brush-border expression and intrinsic factor–cobalamin absorption. Blood 94:3604–3606

    PubMed  CAS  Google Scholar 

  88. Yammani RR, Seetharam S, Seetharam B (2001) Identification and characterization of two distinct ligand binding regions of cubilin. J Biol Chem 276:44777–44784

    Article  PubMed  CAS  Google Scholar 

  89. Zhai XY, Nielsen R, Birn H, Drumm K, Mildenberger S, Freudinger R, Moestrup SK, Verroust PJ, Christensen EI, Gekle M (2000) Cubilin- and megalin-mediated uptake of albumin in cultured proximal tubule cells of opossum kidney. Kidney Int 58:1523–1533

    Article  PubMed  CAS  Google Scholar 

  90. Zheng G, Bachinsky DR, Stamenkovic I, Strickland DK, Brown D, Andres G, McCluskey RT (1994) Organ distribution in rats of two members of the low-density lipoprotein receptor gene family, gp330 and LRP/alpha 2MR, and the receptor-associated protein (RAP). J Histochem Cytochem 42:531–542

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The work was supported in part by the University of Aarhus, and the programs of the European Community, EuReGene (FP6, GA#5085) and EUNEFRON (FP7, GA#201590).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Erik Ilsø Christensen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Christensen, E.I., Verroust, P.J. & Nielsen, R. Receptor-mediated endocytosis in renal proximal tubule. Pflugers Arch - Eur J Physiol 458, 1039–1048 (2009). https://doi.org/10.1007/s00424-009-0685-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-009-0685-8

Keywords

Navigation