Uremia attenuates growth hormone-stimulated insulin-like growth factor-1 expression, a process worsened by inflammation.
Growth hormone (GH) resistance is common in uremia and together with resistance to insulin-like growth factor-1 (IGF-1) contributes to uremic growth retardation and muscle wasting. Previously, we found decreased GH-stimulated janus-kinase 2-signal transducers and activators of transcription 5 (STAT5) phosphorylation and nuclear translocation in uremia; however, it is unclear whether there are more distal defects. Therefore, we tested whether the binding of phosphorylated STAT5b to DNA is intact in uremia. Using uremic rats we found that in addition to impaired hepatic STAT5b phosphorylation, the binding of available phospho-STAT5b to DNA is decreased thus contributing to impaired IGF-1 gene expression. As sepsis-induced inflammation causes a loss of body protein and as Gram-negative infections are relatively common in uremia, we also characterized mechanisms in which acute inflammation might contribute to GH resistance in uremia. Endotoxin-induced inflammation markedly increased the resistance to GH-mediated STAT5b signaling, and further decreased STAT5b binding to DNA and IGF-1 gene expression. These perturbations appear to be related to increased cytokine expression. Thus, our findings indicate that hepatic resistance to GH-induced IGF-1 expression in uremia arises due to defects in STAT5b phosphorylation and its impaired binding to DNA, processes further aggravated by inflammation.
Chen
Yu
Y
Department of Medicine, Stanford University, Stanford, California, USA.
Biada
Jaclyn
J
Sood
Sumita
S
Rabkin
Ralph
R
D000818:Animals; D004247:DNA / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D013006:Growth Hormone / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D019382:Human Growth Hormone / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D014511:Uremia / Q000235:genetics / Q000378:metabolism*
D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D004247:DNA; D053614:Janus Kinase 2