title: Epiphyseal growth plate growth hormone receptor signaling is decreased in chronic kidney disease-related growth retardation.
abstract: Linear growth retardation in children with chronic kidney disease (CKD) has been ascribed to insensitivity to growth hormone. This resistance state has been attributed to impaired growth hormone signaling through the JAK2/STAT5 pathway in liver and skeletal muscle leading to reduced insulin-like growth factor-I (IGF-I). Here we determine whether systemic and growth plate alterations in growth hormone signaling contribute to CKD-induced linear growth retardation using partially nephrectomized and pair-fed control 20-day-old rats. Serum growth hormone did not change in rats with CKD, yet serum IGF-I levels were decreased and growth retarded. The tibial growth plate hypertrophic zone was wider and vascularization at the primary ossification center was reduced in CKD. This was associated with a decrease in growth plate vascular endothelial growth factor (VEGF) mRNA and immunostainable VEGF and IGF-I levels. Growth plate growth hormone receptor and STAT5 protein levels were unchanged, while JAK2 was reduced. Despite comparable growth hormone and growth hormone receptor levels in CKD and control rats, relative STAT5 phosphorylation was significantly depressed in CKD. Of note, the mRNA of SOCS2, an inhibitor of growth hormone signaling, was increased. Thus, linear growth impairment in CKD can in part be explained by impaired long bone growth plate growth hormone receptor signaling through the JAK2/STAT5 pathway, an abnormality that may be caused by an increase in SOCS2 expression.
authors.affiliation: Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Ariel
authors.initials: A
authors.lastname: Troib
authors.forename: Daniel
authors.initials: D
authors.lastname: Landau
authors.forename: Leonid
authors.initials: L
authors.lastname: Kachko
authors.forename: Ralph
authors.initials: R
authors.lastname: Rabkin
authors.forename: Yael
authors.initials: Y
authors.lastname: Segev
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006130:Growth Disorders / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D013006:Growth Hormone / Q000097:blood / Q000378:metabolism*; D006132:Growth Plate / Q000098:blood supply / Q000254:growth & development / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D007668:Kidney / Q000503:physiopathology; D008297:Male; D009392:Nephrectomy; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000150:complications* / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D013977:Tibia / Q000098:blood supply / Q000254:growth & development / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D050799:STAT5 Transcription Factor; C491408:Socs2 protein, rat; D050826:Suppressor of Cytokine Signaling Proteins; D042461:Vascular Endothelial Growth Factor A; C548904:insulin-like growth factor-1, rat; C467498:vascular endothelial growth factor A, rat; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; C507927:Jak2 protein, rat; D053614:Janus Kinase 2