Growth Hormone–Mediated Janus Associated Kinase–Signal Transducers and Activators of Transcription Signaling in the Growth Hormone–Resistant Potassium-Deficient Rat

Abstract

Abstract. Potassium deficiency (KD) is associated with severe growth failure, in part caused by growth hormone (GH) resistance. This study set out to determine whether the resistance could be caused by a defect in GH-mediated janus associated kinasesignal transducers and activators of transcription (STAT) signaling as occurs in uremia. To this end, rats were fed a K-deficient diet for 8 d and pair-fed controls received a K-replete diet. Animals from each group received GH or vehicle, and during this period, KD rats were GH resistant; GH induced body and liver weight gain and linear body growth were severely attenuated in these rats. In addition, signal transduction was studied in the liver of rats that were killed 10 or 15 min after an intravenous GH bolus or vehicle. When the rats were killed, GH receptor mRNA and protein levels were similar in the two groups. The abundance of STAT5, STAT3, and STAT1, proteins that mediate GH signaling, was significantly increased by 40 to 130% in KD. Furthermore, GH induced a far greater increase in STAT5 and STAT3 phosphorylation in this group. STAT5 phosphorylation was enhanced fourfold even when normalized for total STAT5 content. Phosphorylated STAT5 and STAT3 proteins were also increased in nuclear extracts, suggesting normal nuclear translocation of the activated signaling proteins. DNA binding of nuclear STAT5 was unaltered. Thus, in KD, there is resistance to the growth-promoting action of GH despite hyperactivation of the janus associated kinase-STAT signaling pathway. This suggests the presence of a defect distal to the nuclear binding of STAT or, alternatively, a defect in a STAT-independent GH-activated signaling pathway.

Alterations of growth plate and abnormal insulin-like growth factor I metabolism in growth-retarded hypokalemic rats: effect of growth hormone treatment

“…The administration of GH normalized the height of the growth plate and the proliferative activity of chondrocytes but did not accelerate the longitudinal growth rate, did not restore to normal the size of the terminal chondrocytes, and did not increase the local expression of IGF-I mRNA. We did not investigate whether this resistance to GH treatment was mediated by alterations in the GH-activated signaling pathway as it has been found in the liver of potassium-depleted rats (30). According to Schaefer et al (30), the resistance to GH in potassium depletion cannot be accounted for by alterations in the Janus-associated kinase (JAK), signal transducers and activators of transcription (STAT) transduction pathway and presumably arises either because of a distal defect to the binding of STAT to DNA or, alternatively, because of a defect in a STAT-independent GH-activated signaling pathway.…”

Endotoxin attenuates growth hormone-induced hepatic insulin-like growth factor I expression by inhibiting JAK2/STAT5 signal transduction and STAT5b DNA binding

“…Electrophoretic mobility shift assay (EMSA) was performed as described by Ram et al (23) with minor modifications as we described before (26). Nuclear extracts were prepared from 100-mg frozen tissue aliquots using the NE-PER nuclear and cytoplasmic extraction reagents (Pierce Biotechnology, Rockford, IL).…”

Genome-wide analysis of DNA 5-hmC in peripheral blood of uremia by hMeDIP-chip

“…Set out to determine whether the resistance could be caused by a defect in GH-mediated janus associated kinasesignal transducers and activators of transcription (STAT) signaling as occurs in uremia, Schaefer et al 28 conducted the animal experiments and the result suggests the presence of a defect distal to the nuclear binding of STAT or, alternatively, a defect in a STAT-independent GH-activated signaling pathway.…”