title: Cardiac resistance to growth hormone in uremia.
abstract: BACKGROUND
  Cardiovascular disease is a major cause of death in end-stage renal disease (ESRD). Since growth hormone is required for maintaining normal cardiac structure and function and as growth hormone has a salutary effect on cardiac remodeling in disease, we postulated that if cardiac resistance to growth hormone develops in chronic renal failure (CRF) this may predispose to the cardiomyopathy of uremia. We set out to test whether in CRF there is resistance to the cardiac action of growth hormone and whether this defect might be caused by altered growth hormone signaling.
  
  
  METHODS
  Growth hormone-deficient (dw/dw) rats and growth hormone-intact Sprague-Dawley rats underwent a subtotal nephrectomy or sham operation and pair feeding.
  
  
  RESULTS
  In dw/dw rats treated with growth hormone for 8 days there was a significant increase in insulin-like growth factor-1 (IGF-1) mRNA levels in controls but this response was attenuated in CRF. Next, growth hormone-stimulated Janus kinase-signal transducers and activators of transcription (JAK2-STAT5) signaling was studied 15 minutes after intravenous growth hormone in dw/dw and Sprague-Dawley rats. Growth hormone receptor, JAK2, STAT5a, and STAT5b protein levels were unaltered in CRF. Growth hormone-induced JAK2, growth hormone receptor (GHR), and STAT5 tyrosine phosphorylation was significantly depressed in CRF as was nuclear translocation of phosphorylated STAT5. When rats were treated with pharmacologic dose growth hormone, STAT5 phosphorylation increased similarly in CRF and control rats.
  
  
  CONCLUSIONS
  Uremic rats develop cardiac resistance to growth hormone caused at least, in part, by a postreceptor defect in growth hormone-induced signaling that is characterized by impaired phosphorylation and nuclear translocation of STAT5. These findings raise the question whether growth hormone resistance contributes to the cardiac changes of uremia.
authors.affiliation: Research Service, Veterans Affairs Palo Alto Health Care System and Department of Medicine, Stanford University, Palo Alto, California 94304, USA.
authors.forename: Zhilan
authors.initials: Z
authors.lastname: Zheng
authors.forename: Di Fei
authors.initials: DF
authors.lastname: Sun
authors.forename: Padmaja
authors.initials: P
authors.lastname: Tummala
authors.forename: Ralph
authors.initials: R
authors.lastname: Rabkin
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000209:etiology; D002352:Carrier Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000032:analysis / Q000502:physiology; D013006:Growth Hormone / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D053614:Janus Kinase 2; D008297:Male; D008894:Milk Proteins / Q000032:analysis; D009206:Myocardium / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000032:analysis / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011986:Receptors, Somatotropin / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000032:analysis / Q000502:physiology; D014511:Uremia / Q000150:complications / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D011986:Receptors, Somatotropin; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; C491589:Socs1 protein, rat; C494094:Stat5a protein, rat; C494097:Stat5b protein, rat; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D011505:Protein-Tyrosine Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D017027:Protein Tyrosine Phosphatases