Skip to main content

Advertisement

SpringerLink
Log in

Interactions of vitamin D and the proximal tubule

  • Review
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Severe vitamin D deficiency (reduction in serum 25(OH)D concentration) in infants and children can cause features of the Fanconi syndrome, including phosphaturia, glycosuria, aminoaciduria, and renal tubular acidosis. This indicates that vitamin D and its metabolites influence proximal tubule function. Filtered 25(OH)D bound to vitamin D binding protein (DBP) is endocytosed by megalin-cubilin in the apical membrane. Intracellular 25(OH)D is metabolized to 1,25(OH)2D or calcitroic acid by 1-α-hydroxylase or 24-hydroxylase in tubule cell mitochondria. Bone-produced fibroblast growth factor 23 (FGF23) bound to Klotho in tubule cells and intracellular phosphate concentrations are regulators of 1-α-hydroxylase activity and cause proximal tubule phosphaturia. Aminoaciduria occurs when amino acid transporter synthesis is deficient, and 1,25(OH)2D along with retinoic acid up-regulate transporter synthesis by a vitamin D response element in the promoter region of the transporter gene. This review discusses evidence gained from studies in animals or cell lines, as well as from human disorders, that provide insight into vitamin D–proximal tubule interactions.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Chesney RW, Harrison HE (1975) Fanconi syndrome following bowel surgery and hepatitis reversed by 25-hydroxycholecalciferol. J Pediatr 86:857–861

    Article  CAS  PubMed  Google Scholar 

  2. Guignard JP, Torrado A (1973) Proximal renal tubular acidosis in vitamin D deficiency rickets. Acta Paediatr Scand 62:543–546

    Article  CAS  PubMed  Google Scholar 

  3. Curthoys NP, Moe OW (2014) Proximal tubule function and response to acidosis. Clin J Am Soc Nephrol 9:1627–1638

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Dusso AS, Brown AJ, Slatopolsky E (2005) Vitamin D. Am J Physiol Renal Physiol 289:F8–F28

    Article  CAS  PubMed  Google Scholar 

  5. Holick MF (2007) Vitamin D deficiency. N Engl J Med 357:266–281

    Article  CAS  PubMed  Google Scholar 

  6. Christensen EI, Willnow TE (1999) Essential role of megalin in renal proximal tubule for vitamin homeostasis. J Am Soc Nephrol 10:2224–2236

    CAS  PubMed  Google Scholar 

  7. Negri AL (2006) Proximal tubule endocytic apparatus as the specific renal uptake mechanism for vitamin D-binding protein/25-(OH)D3 complex. Nephrology (Carlton) 11:510–515

    Article  CAS  Google Scholar 

  8. Kaseda R, Hosojima M, Sato H, Saito A (2011) Role of megalin and cubilin in the metabolism of vitamin D(3). Ther Apher Dial 15(Suppl 1):14–17

    Article  CAS  PubMed  Google Scholar 

  9. 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 Central  CAS  PubMed  Google Scholar 

  10. Gräsbeck R (2006) Imerslund-Gräsbeck syndrome (selective vitamin B(12) malabsorption with proteinuria). Orphanet J Rare Dis 1:17

    Article  PubMed Central  PubMed  Google Scholar 

  11. Storm T, Zeitz C, Cases O, Amsellem S, Verroust PJ, Madsen M, Benoist JF, Passemard S, Lebon S, Jonsson IM, Emma F, Koldso H, Hertz JM, Nielsen R, Christensen EI, Kozyraki R (2013) Detailed investigations of proximal tubular function in Imerslund-Gräsbeck syndrome. BMC Med Genet 14:111

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Chlon TM, Taffany DA, Welsh J, Rowling MJ (2008) Retinoids modulate expression of the endocytic partners megalin, cubilin, and disabled-2 and uptake of vitamin D-binding protein in human mammary cells. J Nutr 138:1323–1328

    PubMed Central  CAS  PubMed  Google Scholar 

  13. Rowling MJ, Kemmis CM, Taffany DA, Welsh J (2006) Megalin-mediated endocytosis of vitamin D binding protein correlates with 25-hydroxycholecalciferol actions in human mammary cells. J Nutr 136:2754–2759

    PubMed Central  CAS  PubMed  Google Scholar 

  14. Hagenfeldt Y, Berlin T (1992) The human renal 25-hydroxyvitamin D3-1 alpha-hydroxylase: properties studied by isotope-dilution mass spectrometry. Eur J Clin Invest 22:223–228

    Article  CAS  PubMed  Google Scholar 

  15. Yoshida T, Yoshino J, Hayashi M, Saruta T (2002) Identification of a renal proximal tubular cell-specific enhancer in the mouse 25-hydroxyvitamin d 1alpha-hydroxylase gene. J Am Soc Nephrol 13:1455–1463

    Article  CAS  PubMed  Google Scholar 

  16. Perwad F, Portale AA (2011) Vitamin D metabolism in the kidney: regulation by phosphorus and fibroblast growth factor 23. Mol Cell Endocrinol 347:17–24

    Article  CAS  PubMed  Google Scholar 

  17. Weber TJ, Liu S, Indridason OS, Quarles LD (2003) Serum FGF23 levels in normal and disordered phosphorus homeostasis. J Bone Miner Res 18:1227–1234

    Article  CAS  PubMed  Google Scholar 

  18. Monkawa T, Yoshida T, Wakino S, Shinki T, Anazawa H, Deluca HF, Suda T, Hayashi M, Saruta T (1997) Molecular cloning of cDNA and genomic DNA for human 25-hydroxyvitamin D3 1 alpha-hydroxylase. Biochem Biophys Res Commun 239:527–533

    Article  CAS  PubMed  Google Scholar 

  19. St-Arnaud R, Messerlian S, Moir JM, Omdahl JL, Glorieux FH (1997) The 25-hydroxyvitamin D 1-alpha-hydroxylase gene maps to the pseudovitamin D-deficiency rickets (PDDR) disease locus. J Bone Miner Res 12:1552–1559

    Article  CAS  PubMed  Google Scholar 

  20. Ranch D, Zhang MY, Portale AA, Perwad F (2011) Fibroblast growth factor 23 regulates renal 1,25-dihydroxyvitamin D and phosphate metabolism via the MAP kinase signaling pathway in Hyp mice. J Bone Miner Res 26:1883–1890

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Andrukhova O, Zeitz U, Goetz R, Mohammadi M, Lanske B, Erben RG (2012) FGF23 acts directly on renal proximal tubules to induce phosphaturia through activation of the ERK1/2-SGK1 signaling pathway. Bone 51:621–628

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Lindberg K, Amin R, Moe OW, Hu MC, Erben RG, Ostman Wernerson A, Lanske B, Olauson H, Larsson TE (2014) The kidney is the principal organ mediating Klotho effects. J Am Soc Nephrol 25:2169–2175

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Martin A, Quarles LD (2012) Evidence for FGF23 involvement in a bone-kidney axis regulating bone mineralization and systemic phosphate and vitamin D homeostasis. Adv Exp Med Biol 728:65–83

    Article  CAS  PubMed  Google Scholar 

  24. Chanakul A, Zhang MY, Louw A, Armbrecht HJ, Miller WL, Portale AA, Perwad F (2013) FGF-23 regulates CYP27B1 transcription in the kidney and in extra-renal tissues. PLoS One 8:e72816

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Matsumoto T, Ikeda K, Morita K, Fukumoto S, Takahashi H, Ogata E (1987) Blood Ca2+ modulates responsiveness of renal 25(OH)D3-1 alpha-hydroxylase to PTH in rats. Am J Physiol 253:E503–E507

    CAS  PubMed  Google Scholar 

  26. Maiti A, Hait NC, Beckman MJ (2008) Extracellular calcium-sensing receptor activation induces vitamin D receptor levels in proximal kidney HK-2G cells by a mechanism that requires phosphorylation of p38alpha MAPK. J Biol Chem 283:175–183

    Article  CAS  PubMed  Google Scholar 

  27. Fanconi G (1951) Chronic disorders of calcium and phosphate metabolism in children. Schweiz Med Wochenschr 81:908–913

    CAS  PubMed  Google Scholar 

  28. Lightwood R, Stapleton T (1953) Idiopathic hypercalcaemia in infants. Lancet 265:255–256

    Article  CAS  PubMed  Google Scholar 

  29. Schlingmann KP, Kaufmann M, Weber S, Irwin A, Goos C, John U, Misselwitz J, Klaus G, Kuwertz-Broking E, Fehrenbach H, Wingen AM, Guran T, Hoenderop JG, Bindels RJ, Prosser DE, Jones G, Konrad M (2011) Mutations in CYP24A1 and idiopathic infantile hypercalcemia. N Engl J Med 365:410–421

    Article  CAS  PubMed  Google Scholar 

  30. Chen KS, Prahl JM, DeLuca HF (1993) Isolation and expression of human 1,25-dihydroxyvitamin D3 24-hydroxylase cDNA. Proc Natl Acad Sci U S A 90:4543–4547

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Dowen FE, Sayers JA, Hynes AM, Sayer JA (2014) CYP24A1 mutation leading to nephrocalcinosis. Kidney Int 85:1475

    Article  CAS  PubMed  Google Scholar 

  32. Meusburger E, Mundlein A, Zitt E, Obermayer-Pietsch B, Kotzot D, Lhotta K (2013) Medullary nephrocalcinosis in an adult patient with idiopathic infantile hypercalcaemia and a novel CYP24A1 mutation. Clin Kidney J 6:211–215

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Dinour D, Davidovits M, Aviner S, Ganon L, Michael L, Modan-Moses D, Vered I, Bibi H, Frishberg Y, Holtzman EJ (2015) Maternal and infantile hypercalcemia caused by vitamin-D-hydroxylase mutations and vitamin D intake. Pediatr Nephrol 30:145–152

    Article  PubMed  Google Scholar 

  34. 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 Central  CAS  PubMed  Google Scholar 

  35. Genetics Home Reference. Donnai–Barrow syndrome. (2014) http://ghr.nlm.nih.gov/condition/Donnai–Barrow-syndrome. Accessed 12/12/14

  36. Wahlstedt-Froberg V, Pettersson T, Aminoff M, Dugue B, Gräsbeck R (2003) Proteinuria in cubilin-deficient patients with selective vitamin B12 malabsorption. Pediatr Nephrol 18:417–421

    PubMed  Google Scholar 

  37. Orphanet: Proximal renal tubular acidosis. (2014) http://www.orpha.net/consor4.01/www/cgi-bin/OC_Exp.php?lng=EN&Expert=47159 Accessed 10/6/14

  38. Chisolm JJ Jr (1959) The clinical significance of aminoaciduria. J Pediatr 55:303–314

    Article  PubMed  Google Scholar 

  39. Hassanein EA, Patel H (1967) The parathyroid hormone and aminoaciduria in vitamin-D deficiency rickets. Acta Paediatr Scand 56:445–449

    Article  CAS  PubMed  Google Scholar 

  40. Jonxis JH, Huisman TH (1953) Amino-aciduria in rachitic children. Lancet 265:428–431

    Article  CAS  PubMed  Google Scholar 

  41. Fraser D, Kooh SW, Scriver CR (1967) Hyperparathyroidism as the cause of hyperaminoaciduria and phosphaturia in human vitamin D deficiency. Pediatr Res 1:425–435

    Article  CAS  PubMed  Google Scholar 

  42. Harrison HE (1959) Physiology of vitamin D. Helv Paediatr Acta 14:434–446

    CAS  PubMed  Google Scholar 

  43. Scriver CR (1974) Rickets and the pathogenesis of impaired tubular transport of phosphate and other solutes. Am J Med 57:43–49

    Article  CAS  PubMed  Google Scholar 

  44. Grose JH, Scriver CR (1968) Parathyroid-dependent phosphaturia and aminoaciduria in the vitamin D-deficient rat. Am J Physiol 214:370–377

    CAS  PubMed  Google Scholar 

  45. Phillips ME, Havard J, Otterud B (1980) Aminoaciduria in chronic renal failure–its relationship to vitamin D and parathyroid status. Am J Clin Nutr 33:1541–1545

    CAS  PubMed  Google Scholar 

  46. Drezner MK, Feinglos MN (1977) Osteomalacia due to 1alpha,25-dihydroxycholecalciferol deficiency. association with a giant cell tumor of bone. J Clin Invest 60:1046–1053

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Cusworth DC, Dent CE, Scriver CR (1972) Primary hyperparathyroidism and hyperaminoaciduria. Clin Chim Acta 41:355–361

    Article  CAS  PubMed  Google Scholar 

  48. Brodehl J, Kaas WP, Weber HP (1971) Clearance of free amino acids in vitamin D deficiency rickets before and following therapy with vitamin D. Monatsschr Kinderheilkd 119:401–406

    CAS  PubMed  Google Scholar 

  49. Weber HP, Brodehl J, Jakel A (1973) Influence of phosphate load on renal amino-acid transport. Monatsschr Kinderheilkd 121:324–326

    CAS  PubMed  Google Scholar 

  50. Phillips ME (1980) Aminoaciduria–its relationship to vitamin D and parathyroid hormone. Crit Rev Clin Lab Sci 12:215–239

    Article  CAS  PubMed  Google Scholar 

  51. Dabbagh S, Chesney R, Gusowski N, Mathews MC, Padilla M, Theissen M, Slatopolsky E (1989) Aminoaciduria of vitamin D deficiency is independent of PTH levels and urinary cyclic AMP. Miner Electrolyte Metab 15:221–232

    CAS  PubMed  Google Scholar 

  52. Dabbagh S, Gusowski N, Chesney R, Falsetti G, Ellis M, Ellis D (1989) Cyclic AMP does not alter taurine accumulation by rat renal brush border membrane vesicles. Biochem Med Metab Biol 42:132–145

    Article  CAS  PubMed  Google Scholar 

  53. Dabbagh S, Gusowski N, Padilla M, Theissen M, Chesney RW (1990) Perturbation of renal amino acid transport by brush border membrane vesicles in the vitamin D-deficient rat. Biochem Med Metab Biol 44:64–76

    Article  CAS  PubMed  Google Scholar 

  54. Shafeghati Y, Momenin N, Esfahani T, Reyniers E, Wuyts W (2008) Vitamin D-dependent rickets type II: report of a novel mutation in the vitamin D receptor gene. Arch Iran Med 11:330–334

    CAS  PubMed  Google Scholar 

  55. Chesney RW, Han X (2013) Differential regulation of TauT by calcitriol and retinoic acid via VDR/RXR in LLC-PK1 and MCF-7 cells. Adv Exp Med Biol 776:291–305

    Article  CAS  PubMed  Google Scholar 

  56. Carlberg C, Seuter S (2009) A genomic perspective on vitamin D signaling. Anticancer Res 29:3485–3493

    CAS  PubMed  Google Scholar 

  57. Kawashima H, Kraut JA, Kurokawa K (1982) Metabolic acidosis suppresses 25-hydroxyvitamin in D3-1alpha-hydroxylase in the rat kidney. distinct site and mechanism of action. J Clin Invest 70:135–140

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Kraut JA, Gordon EM, Ransom JC, Horst R, Slatopolsky E, Coburn JW, Kurokawa K (1983) Effect of chronic metabolic acidosis on vitamin D metabolism in humans. Kidney Int 24:644–648

    Article  CAS  PubMed  Google Scholar 

  59. Haque SK, Ariceta G, Batlle D (2012) Proximal renal tubular acidosis: a not so rare disorder of multiple etiologies. Nephrol Dial Transplant 27:4273–4287

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Alper SL (2010) Familial renal tubular acidosis. J Nephrol 23(Suppl 16):S57–S76

    PubMed  Google Scholar 

Download references

Acknowledgments

I would like to thank Shermine Dabbaugh, Xiaobin Han, and Andrea B. Patters for their contributions to this manuscript.

Author information

Authors and Affiliations

  1. Department of Pediatrics, The University of Tennessee Health Science Center, and the Children’s Foundation Research Institute at Le Bonheur Children’s Hospital, Memphis, TN, USA

    Russell W. Chesney

Authors
  1. Russell W. Chesney
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Russell W. Chesney.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chesney, R.W. Interactions of vitamin D and the proximal tubule. Pediatr Nephrol 31, 7–14 (2016). https://doi.org/10.1007/s00467-015-3050-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-015-3050-5

Keywords

Search

Navigation