Pediatric Nephrology

, Volume 20, Issue 3, pp 313–318 | Cite as

Growth hormone resistance in uremia, a role for impaired JAK/STAT signaling

  • Ralph Rabkin
  • Di Fei Sun
  • Yu Chen
  • Jane Tan
  • Franz Schaefer
Review

Abstract

Resistance to growth hormone (GH) is a significant complication of advanced chronic renal failure. Thus while the circulating GH levels are normal or even elevated in uremia, resistance to the hormone leads to stunting of body growth in children and contributes to muscle wasting in adults. Insensitivity to GH is the consequence of multiple defects in the GH/insulin-like growth factor-1 (IGF-1) system. Expression of the GH receptor may be reduced, although this is not a consistent finding, GH activation of the Janus kinase 2-signal transducer (JAK2) and activator of transcription (STAT) signal transduction pathway is depressed and this leads to reduced IGF-1 expression, and finally there is resistance to IGF-1, a major mediator of GH action. We review these various defects with an emphasis on the GH-activated JAK2-STAT5 pathway, since this pathway is essential for normal body growth and there has been recent progress in our understanding of the perturbations that occur in uremia.

Keywords

Somatomedin Signal transduction End-stage kidney failure Growth retardation Cachexia Uremia Insulin-like growth factor-1 

References

  1. 1.
    Kaskel F (2003) Chronic renal disease: a growing problem. Kidney Int 64:1141–1151CrossRefGoogle Scholar
  2. 2.
    Tonshoff B, Blum WF, Mehls O (1997) Derangements of the somatotropic hormone axis in chronic renal failure. Kidney Int [Suppl] 58:S106–113Google Scholar
  3. 3.
    Wuhl E, Schaefer F (2002) Effects of growth hormone in patients with chronic renal failure: experience in children and adults. Horm Res 58 [Suppl] 3:35–38Google Scholar
  4. 4.
    Rabkin R (2003) Therapeutic use of growth factors in renal disease. In: Kopple JD, Massry SG (eds) Kopple and Massry’s nutritional management of renal disease. Lipincott and Williams and Wilkins, Philadelphia, pp 581–592Google Scholar
  5. 5.
    Schaefer F, Rabkin R (2003) Insulin-like growth factor and the kidney. In: LeRoith WZD, Baxter RC (eds) Insulin-like growth factors. Kluwer, New York, pp 244–255Google Scholar
  6. 6.
    Woelfle J, Chia DJ, Rotwein P (2003) Mechanisms of growth hormone (GH) action. Identification of conserved Stat5 binding sites that mediate GH-induced insulin-like growth factor-I gene activation. J Biol Chem 278:51261–51266Google Scholar
  7. 7.
    Teglund S, McKay C, Schuetz E, Deursen JM van, Stravopodis D, Wang D, Brown M, Bodner S, Grosveld G, Ihle JN (1998) Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses. Cell 93:841–850CrossRefPubMedGoogle Scholar
  8. 8.
    Rabkin R, Guest S, Schaefer F (2004) The kidney and the insulin-like growth factor system in health and disease. In: Houston M, Holly J, Feldman E, Totawa NJ (eds) IGF and nutrition in health and disease. Humana, pp 227–247Google Scholar
  9. 9.
    Roelfsema V, Clark RG (2001) The growth hormone and insulin-like growth factor axis: its manipulation for the benefit of growth disorders in renal failure. J Am Soc Nephrol 12:1297–1306Google Scholar
  10. 10.
    Pombo M, Pombo CM, Garcia A, Caminos E, Gualillo O, Alvarez CV, Casanueva FF, Dieguez C (2001) Hormonal control of growth hormone secretion. Horm Res 55 [Suppl] 1:11–16Google Scholar
  11. 11.
    Butler AA, Le Roith D (2001) Control of growth by the somatropic axis: growth hormone and the insulin-like growth factors have related and independent roles. Annu Rev Physiol 63:141–164CrossRefGoogle Scholar
  12. 12.
    Feneberg R, Schaefer F, Veldhuis JD (2003) Neuroendocrine adaptations in renal disease. Pediatr Nephrol 18:492–497Google Scholar
  13. 13.
    Schaefer F, Veldhuis JD, Stanhope R, Jones J, Scharer K (1994) Alterations in growth hormone secretion and clearance in peripubertal boys with chronic renal failure and after renal transplantation. Cooperative Study Group of Pubertal development in Chronic Renal Failure. J Clin Endocrinol Metab 78:1298–1306CrossRefGoogle Scholar
  14. 14.
    Tonshoff B, Veldhuis JD, Heinrich U, Mehls O (1995) Deconvolution analysis of spontaneous nocturnal growth hormone secretion in prepubertal children with preterminal chronic renal failure and with end-stage renal disease. Pediatr Res 37:86–93Google Scholar
  15. 15.
    Veldhuis JD, Iranmanesh A, Wilkowski MJ, Samojlik E (1994) Neuroendocrine alterations in the somatotropic and lactotropic axes in uremic men. Eur J Endocrinol 131:489–498Google Scholar
  16. 16.
    Ramirez G, Bercu BB, Bittle PA, Ayers CW, Ganguly A (1990) Response to growth hormone-releasing hormone in adult renal failure patients on hemodialysis. Metabolism 39:764–768CrossRefGoogle Scholar
  17. 17.
    Garcia E, Santos F, Rodriguez J, Martinez V, Rey C, Veldhuis J, Krieg RJ Jr (1997) Impaired secretion of growth hormone in experimental uremia: relevance of caloric deficiency. Kidney Int 52:648–653Google Scholar
  18. 18.
    Metzger DL, Kerrigan JR, Krieg RJ Jr, Chan JC, Rogol AD (1993) Alterations in the neuroendocrine control of growth hormone secretion in the uremic rat. Kidney Int 43:1042–1048Google Scholar
  19. 19.
    Haffner D, Schaefer F, Girard J, Ritz E, Mehls O (1994) Metabolic clearance of recombinant human growth hormone in health and chronic renal failure. J Clin Invest 93:1163–1171Google Scholar
  20. 20.
    Blum WF (1991) Insulin-like growth factors (IGFs) and IGF binding proteins in chronic renal failure: evidence for reduced secretion of IGFs. Acta Paediatr Scand [Suppl] 379:24–31Google Scholar
  21. 21.
    Fouque D, Peng SC, Kopple JD (1995) Pharmacokinetics of recombinant human insulin-like growth factor-1 in dialysis patients. Kidney Int 47:869–875Google Scholar
  22. 22.
    Rabkin R, Fervenza FC, Maidment H, Ike J, Hintz R, Liu F, Bloedow DC, Hoffman AR, Gesundheit N (1996) Pharmacokinetics of insulin-like growth factor-1 in advanced chronic renal failure. Kidney Int 49:1134–1140Google Scholar
  23. 23.
    Tonshoff B, Powell DR, Zhao D, Durham SK, Coleman ME, Domene HM, Blum WF, Baxter RC, Moore LC, Kaskel FJ (1997) Decreased hepatic insulin-like growth factor (IGF)-I and increased IGF binding protein-1 and -2 gene expression in experimental uremia. Endocrinology 138:938–946CrossRefGoogle Scholar
  24. 24.
    Hanna JD, Santos F, Foreman JW, Chan JC, Han VK (1995) Insulin-like growth factor-I gene expression in the tibial epiphyseal growth plate of growth hormone-treated uremic rats. Kidney Int 47:1374–1382PubMedGoogle Scholar
  25. 25.
    Schaefer F, Chen Y, Tsao T, Nouri P, Rabkin R (2001) Impaired JAK-STAT signal transduction contributes to growth hormone resistance in chronic uremia. J Clin Invest 108:467–475CrossRefGoogle Scholar
  26. 26.
    Sun D, Zheng Z, Tummala P, Oh J, Schaefer F, Rabkin R (2004) Chronic uremia attenuates growth hormone induced signal transduction in skeletal muscle. J Am Soc Nephrol 15:2630–2636CrossRefGoogle Scholar
  27. 27.
    Zheng Z, Sun D, Tummala P, Rabkin R (2005) Cardiac resistance to growth hormone in uremia. Kidney Int (in press)Google Scholar
  28. 28.
    Tonshoff B, Eden S, Weiser E, Carlsson B, Robinson IC, Blum WF, Mehls O (1994) Reduced hepatic growth hormone (GH) receptor gene expression and increased plasma GH binding protein in experimental uremia. Kidney Int 45:1085–1092Google Scholar
  29. 29.
    Edmondson SR, Baker NL, Oh J, Kovacs G, Werther GA, Mehls O (2000) Growth hormone receptor abundance in tibial growth plates of uremic rats: GH/IGF-I treatment. Kidney Int 58:62–70CrossRefPubMedGoogle Scholar
  30. 30.
    Villares SM, Goujon L, Maniar S, Delehaye-Zervas MC, Martini JF, Kleincknecht C, Postel-Vinay MC (1994) Reduced food intake is the main cause of low growth hormone receptor expression in uremic rats. Mol Cell Endocrinol 106:51–56CrossRefGoogle Scholar
  31. 31.
    Baumann G (2001) Growth hormone binding protein 2001. J Pediatr Endocrinol Metab 14:355–375Google Scholar
  32. 32.
    Baumann G (2002) Growth hormone binding protein. The soluble growth hormone receptor. Minerva Endocrinol 27:265–276Google Scholar
  33. 33.
    Tonshoff B, Cronin MJ, Reichert M, Haffner D, Wingen AM, Blum WF, Mehls O (1997) Reduced concentration of serum growth hormone (GH)-binding protein in children with chronic renal failure: correlation with GH insensitivity. The European Study Group for Nutritional Treatment of Chronic Renal Failure in Childhood. The German Study Group for Growth Hormone Treatment in Chronic Renal Failure. J Clin Endocrinol Metab 82:1007–1013CrossRefGoogle Scholar
  34. 34.
    Baumann G (1996) Growth hormone binding protein and free growth hormone in chronic renal failure. Pediatr Nephrol 10:328–330Google Scholar
  35. 35.
    Postel-Vinay MC, Tar A, Crosnier H, Broyer M, Rappaport R, Tonshoff B, Mehls O (1991) Plasma growth hormone-binding activity is low in uraemic children. Pediatr Nephrol 5:545–547Google Scholar
  36. 36.
    Powell DR, Liu F, Baker BK, Hintz RL, Lee PD, Durham SK, Brewer ED, Frane JW, Watkins SL, Hogg RJ (1997) Modulation of growth factors by growth hormone in children with chronic renal failure. The Southwest Pediatric Nephrology Study Group. Kidney Int 51:1970–1979Google Scholar
  37. 37.
    Greenstein J, Guest S, Tummala P, Tan J, Rabkin R (2003) Growth hormone receptor expression in uremia. J Am Soc Nephrol SA–PO1085Google Scholar
  38. 38.
    Fisker S, Vahl N, Jorgensen JO, Christiansen JS, Orskov H (1997) Abdominal fat determines growth hormone-binding protein levels in healthy nonobese adults. J Clin Endocrinol Metab 82:123–128CrossRefGoogle Scholar
  39. 39.
    Fisker S, Hansen B, Fuglsang J, Kristensen K, Ovesen P, Orskov H, Jorgensen JO (2004) Gene expression of the GH receptor in subcutaneous and intraabdominal fat in healthy females: relationship to GH-binding protein. Eur J Endocrinol 150:773–777CrossRefGoogle Scholar
  40. 40.
    Fisker S, Kristensen K, Rosenfalck AM, Pedersen SB, Ebdrup L, Richelsen B, Hilsted J, Christiansen JS, Jorgensen JO (2001) Gene expression of a truncated and the full-length growth hormone (GH) receptor in subcutaneous fat and skeletal muscle in GH-deficient adults: impact of GH treatment. J Clin Endocrinol Metab 86:792–796CrossRefGoogle Scholar
  41. 41.
    Piwien-Pilipuk G, Huo JS, Schwartz J (2002) Growth hormone signal transduction. J Pediatr Endocrinol Metab 15:771–786Google Scholar
  42. 42.
    Wormald S, Hilton DJ (2004) Inhibitors of cytokine signal transduction. J Biol Chem 279:821–824CrossRefGoogle Scholar
  43. 43.
    Woelfle J, Billiard J, Rotwein P (2003) Acute control of insulin-like growth factor-I gene transcription by growth hormone through Stat5b. J Biol Chem 278:22696–22702Google Scholar
  44. 44.
    Woelfle J, Rotwein P (2003) In vivo regulation of growth hormone-stimulated gene transcription by STAT5b. Am J Physiol Endocrinol Metab 286:E393–401CrossRefGoogle Scholar
  45. 45.
    Yoshimura A, Mori H, Ohishi M, Aki D, Hanada T (2003) Negative regulation of cytokine signaling influences inflammation. Curr Opin Immunol 15:704–708CrossRefGoogle Scholar
  46. 46.
    Greenhalgh CJ, Bertolino P, Asa SL, Metcalf D, Corbin JE, Adams TE, Davey HW, Nicola NA, Hilton DJ, Alexander WS (2002) Growth enhancement in suppressor of cytokine signaling 2 (SOCS-2)-deficient mice is dependent on signal transducer and activator of transcription 5b (STAT5b). Mol Endocrinol 16:1394–1406CrossRefPubMedGoogle Scholar
  47. 47.
    Kaysen GA (2001) The microinflammatory state in uremia: causes and potential consequences. J Am Soc Nephrol 12:1549–1557PubMedGoogle Scholar
  48. 48.
    Powell DR, Liu F, Baker BK, Hinzt 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 14:579–583Google Scholar
  49. 49.
    Ding H, Gao XL, Hirschberg R, Vadgama JV, Kopple JD (1996) Impaired actions of insulin-like growth factor 1 on protein synthesis and degradation in skeletal muscle of rats with chronic renal failure. Evidence for a postreceptor defect. J Clin Invest 97:1064–1075Google Scholar
  50. 50.
    Tsao T, Fervenza F, Friedlaender M, Chen Y, Rabkin R (2002) Effect of prolonged uremia on insulin-like growth factor-I receptor autophosphorylation and tyrosine kinase activity in kidney and muscle. Exp Nephrol 10:285–292CrossRefGoogle Scholar
  51. 51.
    Cecchin F, Ittoop O, Sinha MK, Caro JF (1988) Insulin resistance in uremia: insulin receptor kinase activity in liver and muscle from chronic uremic rats. Am J Physiol 254:E394–E401Google Scholar
  52. 52.
    Friedman JE, Dohm GL, Elton CW, Rovira A, Chen JJ, Leggett-Frazier N, Atkinson SM Jr, Thomas FT, Long SD, Caro JF (1991) Muscle insulin resistance in uremic humans: glucose transport, glucose transporters, and insulin receptors. Am J Physiol 261:E87–E94Google Scholar

Copyright information

© IPNA 2005

Authors and Affiliations

  • Ralph Rabkin
    • 1
    • 2
    • 4
  • Di Fei Sun
    • 2
  • Yu Chen
    • 2
  • Jane Tan
    • 2
  • Franz Schaefer
    • 3
  1. 1.Veterans AffairsPalo Alto Health Care SystemPalo AltoUSA
  2. 2.Department of MedicineStanford UniversityStanfordUSA
  3. 3.Division of Pediatric NephrologyUniversity Children’s HospitalHeidelbergGermany
  4. 4.Veterans AffairsPalo Alto Health Care System 111RPalo AltoUSA

Personalised recommendations