Impaired JAK-STAT signal transduction contributes to growth hormone resistance in chronic uremia.
Chronic renal failure (CRF) is associated with resistance to the growth-promoting and anabolic actions of growth hormone (GH). In rats with CRF induced by partial renal ablation, 7 days of GH treatment had a diminished effect on weight gain and hepatic IGF-1 and IGFBP-1 mRNA levels, compared with sham-operated pair-fed controls. To assess whether GH resistance might be due to altered signal transduction, activation of the JAK-STAT pathway was studied 10 or 15 minutes after intravenous injection of 5 mg/kg GH or vehicle. Hepatic GH receptor (GHR) mRNA levels were significantly decreased in CRF, but GHR protein abundance and GH binding to microsomal and plasma membranes was unaltered. JAK2, STAT1, STAT3, and STAT5 protein abundance was also unchanged. However, GH-induced tyrosine phosphorylation of JAK2, STAT5, and STAT3 was 75% lower in the CRF animals. Phosphorylated STAT5 and STAT3 were also diminished in nuclear extracts. The expression of the suppressor of cytokine signaling-2 (SOCS-2) was increased twofold in GH-treated CRF animals, and SOCS-3 mRNA levels were elevated by 60% in CRF, independent of GH treatment. In conclusion, CRF causes a postreceptor defect in GH signal transduction characterized by impaired phosphorylation and nuclear translocation of GH-activated STAT proteins, which is possibly mediated, at least in part, by overexpression of SOCS proteins.
Schaefer
F
F
Research Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304, USA.
Chen
Y
Y
Tsao
T
T
Nouri
P
P
Rabkin
R
R
D000818:Animals; D004351:Drug Resistance; D004435:Eating / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006130:Growth Disorders / Q000209:etiology; D019382:Human Growth Hormone / Q000494:pharmacology*; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D053614:Janus Kinase 2; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014511:Uremia / Q000150:complications / Q000503:physiopathology*; D015430:Weight Gain / Q000187:drug effects
D018970:Insulin-Like Growth Factor Binding Protein 1; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507927:Jak2 protein, rat; D053614:Janus Kinase 2