Skip to main content

Advertisement

SpringerLink
Log in

IGF-binding protein-3 fragments in plasma of a child with acute renal failure

  • Brief Report
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

The insulin-like growth factors (IGF) -I and -II promote cellular growth and differentiation of various organs. Their growth-stimulating effects are modulated by a family of six IGF-binding proteins (IGFBPs). Altered patterns of intact and fragmented IGFBPs have been reported in serum and urine of children with chronic renal failure (CRF), and it has been suggested that this may contribute to the growth failure observed in these patients. In the present study, a rapid and comprehensive method is presented to analyze IGFBPs and IGFBP fragments in the plasma of a child with acute renal failure (ARF) who had undergone plasmapheresis. The plasma IGF-I and IGFBP-3 levels were drastically reduced. Plasmapheresis filtrate (3 l) was fractionated by cation-exchange chromatography and reversed-phase high-performance liquid chromatography. The fractions obtained were tested by ligand and immunoblotting. In addition to IGFBP-1 and -4 fragments, the majority of IGF-binding polypeptides were IGFBP-3 immunoreactive. N-terminal sequence analysis of a 17-kDa polypeptide revealed the isolation of a C-terminal fragment of IGFBP-3 starting with Lys 160. The IGF-II-binding polypeptide pattern in the ARF plasma resembles the pattern in hemofiltrate from CRF patients, suggesting that similar or identical proteases are involved in IGFBP-3 fragmentation and common mechanisms may lead to the accumulation of the fragments in both diseases.

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 A-C
Fig. 2
Fig. 3 A,B
Fig. 4 A,B
Fig. 5 A,B
Fig. 6

References

  1. Mohan S, Baylink DJ (2002) IGF-binding proteins are multifunctional and act via IGF-dependent and -independent mechanisms. J Endocrinol 175:19–31

    CAS  PubMed  Google Scholar 

  2. Baxter RC (2000) Insulin-like growth factor (IGF) binding proteins: interactions with IGFs and intrinsic bioactivities. Am J Physiol Endocrinol Metab 278:E967–E976

    CAS  PubMed  Google Scholar 

  3. Maile LA, Holly JMP (1999) Insulin-like growth factor binding protein (IGFBP) proteolysis: occurrence, identification, role and regulation. Growth Horm IGF Res 9:85–95

    Article  CAS  Google Scholar 

  4. Zadeh SM, Binoux M (1997) The 16-kDa proteolytic fragment of insulin-like growth factor (IGF) binding protein-3 inhibits the mitogenic action of fibroblast growth factor on mouse fibroblasts with a targeted disruption of the type 1 IGF receptor gene. Endocrinology 138:3069–3072

    Article  CAS  PubMed  Google Scholar 

  5. Vorwerk P, Yamanaka Y, Spagnoli A, Oh Y, Rosenfeld RG (1998) Insulin and IGF binding by IGFBP-3 fragments derived from proteolysis, baculovirus expression and normal human urine. J Clin Endocrinol Metab 83:1392–1395

    Article  CAS  PubMed  Google Scholar 

  6. Shi Z, Xu W, Loechel F, Wewer UM, Murphy LJ (2000) ADAM 12, a Disintegrin Metalloprotease, interacts with insulin-like growth factor binding protein-3. J Biol Chem 275:18574–18580

    Article  CAS  PubMed  Google Scholar 

  7. Byun D, Mohan S, Yoo M, Sexton C, Baylink DJ, Qin X (2001) Pregnancy-associated plasma protein-A accounts for the insulin-like growth factor (IGF) binding protein-4 (IGFBP-4) proteolytic activity in human pregnancy serum and enhances the mitogenic activity of IGF by degrading IGFBP-4 in vitro. J Clin Endocrinol Metab 86:847–854

    Article  CAS  PubMed  Google Scholar 

  8. Hossenlopp P, Segovia B, Lassare C, Roghani M, Bredon M, Binoux M (1990) Evidence of enzymatic degradation of insulin-like growth factor-binding proteins in the 150 K complex during pregnancy. J Clin Endocrinol Metab 71:797–805

    CAS  PubMed  Google Scholar 

  9. Giudice LC, Farrell EM, Pham H, Lamson G, Rosenfeld RG (1990) Insulin-like growth factor binding proteins in maternal serum throughout gestation and in the puerperium; effects of a pregnancy-associated serum protease activity. J Clin Endocrinol Metab 71:806–816

    CAS  PubMed  Google Scholar 

  10. Kübler B, Cowell S, Zapf J, Braulke T (1998) Proteolysis of insulin-like growth factor binding proteins by a novel 50-kilodalton metalloproteinase in human pregnancy serum. Endocrinology 139:156–163

    Article  PubMed  Google Scholar 

  11. Bereket A, Lang CH, Blethen SL, Fan J, Frost RA, Wilson TA (1995) Insulin-like growth factor binding protein-3 proteolysis in children with insulin-dependent diabetes mellitus: a possible role for insulin in the regulation of IGFBP-3 protease activity. J Clin Endocrinol Metab 80:2282–2288

    Article  CAS  PubMed  Google Scholar 

  12. Whellams EJ, Maile LA, Fernihough JK, Billingham MEJ, Holly JMP (2000) Alterations in insulin-like growth factor binding protein-3 proteolysis and complex formation in the arthritic joint. J Endocrinol 165:545–556

    CAS  PubMed  Google Scholar 

  13. Powell DR, Rosenfeld RG, Sperry JB, Baker BK, Hintz RL (1987) Serum concentrations of insulin-like growth factor (IGF)-1, IGF-2 and unsaturated somatomedin carrier proteins in children with chronic renal failure. Am J Kidney Dis 10:287–292

    CAS  PubMed  Google Scholar 

  14. Blum WF, Ranke MB, Kietzmann K, Tönshoff B, Mehls O (1991) Growth hormone resistance and inhibition of somatomedin activity by excess of insulin-like growth factor binding protein in uremia. Pediatr Nephrol 5:539–544

    CAS  PubMed  Google Scholar 

  15. Tönshoff B, Blum WF, Wingen AM, Mehls O (1995) Serum insulin-like growth factors (IGFs) and IGF binding proteins 1, 2, and 3 in children with chronic renal failure: relationship to height and glomerular filtration rate. The European Study Group for Nutritional Treatment of Chronic Renal Failure in Childhood. J Clin Endocrinol Metab 80:2684–2691

    Article  PubMed  Google Scholar 

  16. Powell DR, Liu F, Baker BK, Hintz RL, Durham SK, Brewer ED, Frane JW, Tönshoff B, Mehls O, Wingen AM, Watkins SL, Hogg RJ, Lee PD (1997) Insulin-like growth factor-binding protein-6 levels are elevated in serum of children with chronic renal failure: a report of the Southwest Pediatric Nephrology Study Group. Clin Endocrinol Metab 82:2978–2984

    Article  CAS  Google Scholar 

  17. Powell DR, Durham SK, Brewer ED, Frane JW, Watkins SL, Hogg RJ, Mohan S (1999) Effects of chronic renal failure and growth hormone on serum levels of insulin-like growth factor-binding protein-4 (IGFBP-4) and IGFBP-5 in children: a report of the Southwest Pediatric Nephrology Study Group. J Clin Endocrinol Metab 84:596–601

    Article  CAS  PubMed  Google Scholar 

  18. Powell DR, Durham SK, Liu F, Baker BK, Lee PD, Watkins SL, Campbell PG, Brewer ED, Hintz RL, Hogg RJ (1998) The insulin-like growth factor axis and growth in children with chronic renal failure: a report of the Southwest Pediatric Nephrology Study Group. J Clin Endocrinol Metab 83:1654–1661

    Article  CAS  PubMed  Google Scholar 

  19. Kübler B, Dräger C, John H, Andag U, Scharf JG, Forssmann WG, Braulke T, Ständker L (2002) Isolation and characterization of circulating fragments of the insulin-like growth factor binding protein-3. FEBS Lett 518:124–128

    Article  PubMed  Google Scholar 

  20. Lee DY, Park SK, Yorgin PD, Cohen P, Oh Y, Rosenfeld RG (1994) Alteration in insulin-like growth factor binding proteins (IGFBPs) and IGFBP-3 protease activity in serum and urine from acute and chronic renal failure. J Clin Endocrinol Metab 79:1376–1382

    Article  CAS  PubMed  Google Scholar 

  21. Tönshoff B, Mehls O, Heinrich U, Blum WF, Ranke MB, Schauer A (1990) Growth stimulating effects of recombinant human growth hormone in children with end-stage renal disease. J Pediatr 116:561–566

    PubMed  Google Scholar 

  22. Ständker L, Wobst P, Mark S, Forssmann WG (1998) Isolation and characterization of circulating 13-kDa C-terminal fragments of human insulin-like growth factor binding protein-5. FEBS Lett 41:281–286

    Google Scholar 

  23. Ständker L, Braulke T, Mark S, Mostafavi H, Meyer M, Höning S, Gimenez-Gallego G, Forssmann WG (2000) Partial IGF affinity of circulating N- and C-terminal fragments of human insulin-like growth factor binding protein-4 (IGFBP-4) and the disulfide bonding pattern of the C-terminal IGFBP-4 domain. Biochemistry 39:5082–5088

    Article  PubMed  Google Scholar 

  24. Ulinski T, Mohan S, Kiepe D, Blum WF, Wingen AM, Mehls O, Tönshoff B (2000) Serum insulin-like growth factor binding protein (IGFBP)-4 and IGFBP-5 in children with chronic renal failure: relationship to growth and glomerular filtration rate. Pediatr Nephrol 14:589–597

    Article  CAS  PubMed  Google Scholar 

  25. Ständker L, Kübler B, Obendorf M, Braulke T, Forssmann WG, Mark S (2003) In vivo processed fragments of IGF binding protein-2 co-purified with bioactive IGF-II. Biochem Biophys Res Commun 304:708–713

    Article  PubMed  Google Scholar 

  26. Mark S, Forssmann WG, Ständker L (1999) Strategy for identifying circulating fragments of insulin-like growth factor binding proteins in a hemofiltrate peptide bank. J Chromatogr A 852:197–205

    Article  CAS  PubMed  Google Scholar 

  27. Schulz-Knappe P, Schrader M, Ständker L, Richter R, Hess R, Jurgens M, Forssmann WG (1997) Peptide bank generated by large-scale preparation of circulating human peptides. J Chromatogr A 776:125–132

    Article  CAS  PubMed  Google Scholar 

  28. Blum WF, Breier BH (1994) Radioimmunoassays for IGFs and IGFBPs. Growth Regul [Suppl 1] 4:11–19

  29. Blum WF, Ranke MB, Kietzmann K, Gauggel E, Zeisel HJ, Bierich JR (1990) A specific radioimmunoassay for the growth hormone (GH)-dependent somatomedin-binding protein: its use for diagnosis of GH deficiency. J Clin Endocrinol Metab 70:1292–1298

    CAS  PubMed  Google Scholar 

  30. Schägger H, Jagow G von (1987) Tricine-sodium dodecyl sulfate-polyacrylamide gel electrophoresis for the separation of proteins in the range from 1 to 100 kDa. Anal Biochem 166:10217–10224

    Google Scholar 

  31. Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685

    PubMed  Google Scholar 

  32. Parker KC, Strominger JC (1983) Localization of the sites of iodination of human β2-microglobulin: quarternary structure implications for histocompatibility antigens. Biochemistry 22:1145–1153

    CAS  PubMed  Google Scholar 

  33. Shalamanova L, Kübler B, Scharf JG, Braulke T (2001) MDCK cells secrete neutral proteases cleaving insulin-like growth factor-binding protein 2-6. Am J Physiol Endocrinol Metab 281:E1221–E1229

    CAS  PubMed  Google Scholar 

  34. Hirschberg R, Adler S (1998) Insulin-like growth factor system and the kidney: physiology, pathophysiology, and therapeutic implications. Am J Kidney Dis 31:901–919

    CAS  PubMed  Google Scholar 

  35. Powell DR, Liu F, Baker BK, Hintz RL, Kale A, Suwanichkul A, Durham SK (2000) Effect of chronic renal failure and growth hormone therapy on the insulin-like growth factors and their binding proteins. Pediatr Nephrol 14:579–583

    Article  CAS  PubMed  Google Scholar 

  36. Booth AD, Firth JD, Jayne DR (2003) Immunotherapy for autoimmune and inflammatory renal diseases. Expert Opin Biol Ther 3:487–500

    Article  CAS  PubMed  Google Scholar 

  37. Firth SM, Baxter RC (1999) Characterisation of recombinant glycosylation variants of insulin-like growth factor binding protein-3. J Endocrinol 160:379–387

    CAS  PubMed  Google Scholar 

  38. Binoux M, Lalou C, Mohseni-Zadeh S, Angelloz-Nicoud P, Daubas C, Babajko S (1998) Proteolytic fragments of IGF binding protein-3: physiological significance. In: Takano K, Hizuka N, Takahashi S (eds) Molecular mechanisms to regulate the activities of insulin-like growth factors. Elsevier, Amsterdam, pp 99–106

  39. Kiepe D, Andress DL, Mohan S, Ständker L, Ulinski T, Himmele R, Mehls O, Tönshoff B (2001) Intact IGF-binding protein-4 and −5 and their respective fragments isolated from chronic renal failure serum differentially modulate IGF-I actions in cultured growth plate chondrocytes. J Am Soc Nephrol 12:2400–2410

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr. Silke Mark and Dr. Wolf-Georg Forssmann for experimental support and helpful discussions, Jutta Barras-Aknoukh and Daniela Zoch for excellent technical assistance, and Cyrilla Maelicke for the help with the manuscript.

Author information

Authors and Affiliations

  1. Department of Biochemistry, Children’s Hospital, University Hospital Hamburg Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany

    Victoria Schebek-Fürstenberg, Dirk E. Müller-Wiefel, Thomas Braulke & Bernd Kübler

  2. IPF Pharmaceuticals, 30625 Hannover, Germany

    Ludger Ständker & Wilfried Hahn

  3. Immunology Department, University of Göttingen, 37075 Göttingen, Germany

    Martin Oppermann

  4. Eli Lilly, 61350 Bad Homburg, Germany

    Werner F. Blum

  5. University Children’s Hospital, 35392 Giessen, Germany

    Werner F. Blum

Authors
  1. Victoria Schebek-Fürstenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ludger Ständker
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Martin Oppermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dirk E. Müller-Wiefel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wilfried Hahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Werner F. Blum
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Thomas Braulke
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bernd Kübler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bernd Kübler.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schebek-Fürstenberg, V., Ständker, L., Oppermann, M. et al. IGF-binding protein-3 fragments in plasma of a child with acute renal failure. Pediatr Nephrol 19, 1418–1425 (2004). https://doi.org/10.1007/s00467-004-1622-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-004-1622-x

Keywords

Search

Navigation