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Impaired JAK-STAT signal transduction contributes to growth hormone resistance in chronic uremia

F Schaefer1, Y Chen, T Tsao

  • 1Research Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304, USA.

The Journal of Clinical Investigation
|August 8, 2001
PubMed

Insights

Chronic renal failure (CRF) causes growth hormone (GH) resistance due to impaired signal transduction. This study found reduced JAK-STAT pathway activation in rats with CRF, suggesting a postreceptor defect.

Area of Science:

  • Endocrinology
  • Nephrology
  • Molecular Biology

Background:

  • Chronic renal failure (CRF) is linked to resistance to growth hormone (GH) effects.
  • GH resistance in CRF may stem from altered signal transduction pathways.

Purpose of the Study:

  • To investigate the JAK-STAT signaling pathway's role in GH resistance in CRF.
  • To determine if CRF affects GH receptor expression and downstream signaling.

Main Methods:

  • CRF was induced in rats via partial renal ablation.
  • GH signaling was assessed by measuring JAK-STAT pathway activation post-GH injection.
  • GH receptor (GHR) and suppressor of cytokine signaling (SOCS) protein/mRNA levels were quantified.

Main Results:

  • GH treatment showed diminished effects on weight gain and hepatic gene expression in CRF rats.
  • Hepatic GHR mRNA was decreased in CRF, but GHR protein and GH binding were unchanged.
  • GH-induced tyrosine phosphorylation of JAK2, STAT5, and STAT3 was significantly reduced in CRF.
  • Nuclear translocation of phosphorylated STAT5 and STAT3 was diminished in CRF.
  • SOCS-2 and SOCS-3 expression was elevated in CRF rats.

Conclusions:

  • CRF induces a postreceptor defect in GH signal transduction.
  • Impaired STAT protein phosphorylation and nuclear translocation contribute to GH resistance in CRF.
  • Overexpression of SOCS proteins may mediate this GH signaling defect in CRF.

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