Cardiac resistance to growth hormone in uremia

doi:doi:10.1111/j.1523-1755.2005.00150.x

Abstract

Cardiac resistance to growth hormone in uremia.

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.

Conclusion

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.

Keywords:

somatotropin, IGF-1, JAK2, STAT5, signal transduction, kidney failure, heart

Hormones – Cytokines – Signalling