Hormones – Cytokines – Signalling
Kidney International (2003) 64, 421–430; doi:10.1046/j.1523-1755.2003.00117.x
Regulation of growth-hormone-receptor gene expression by growth hormone and pegvisomant in human mesangial cells
Udo Meinhardt, Andrée Eblé, Amélie Besson, Christian J Strasburger, Jean-Daniel Sraer and Primus E Mullis
Paediatric Endocrinology, University Children's Hospital, Inselspital, Bern, Switzerland; Medizinische Klinik Innenstadt, Ludwig-Maximillians-Universität, Munich, Germany; and Service Nephrologie A, Hôpital Tenon, Paris, France
Correspondence: Prof Dr med Primus E. Mullis, M.D., University Children's Hospital, Inselspital, CH-3010 Bern, Switzerland. E-mail: primus.mullis@insel.ch
Received 30 August 2002; Revised 4 November 2002; Re-revised 26 February 2003; Re-revised 17 March 2003; Accepted 28 March 2003.
Abstract
Regulation of growth-hormone-receptor gene expression by growth hormone and pegvisomant in human mesangial cells.
Background
Mice transgenic for growth hormone develop mesangial proliferation, glomerular hypertrophy, and progressive glomerular sclerosis suggesting that the growth hormone–insulin-like growth factor I (IGF-I) pathway plays an important role. Therefore, we studied the impact of variable concentrations of 22 kD, 20 kD growth hormone, as well as of the growth hormone receptor antagonist pegvisomant (B2036-PEG), on both the growth hormone receptor (GHR/GHBP) gene expression and growth hormone binding protein (GHBP) formation in a human glomerular mesangial cell line. Further, the impact on collagen, IGF-I and IGF binding protein-1 (IGFBP-1) formation was studied.
Methods
In order to assess transcription, quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used.
Results
Physiologic doses of 22 kD or 20 kD growth hormone caused a dose-dependent and significant (P < 0.01) up-regulation of GHR/GHBP gene transcription, whereas supraphysiologic doses (50 and 500 ng/mL) resulted in down-regulation (P < 0.001). Whenever pegvisomant was used, there was no increase in GHR/GHBP expression. These data were confirmed using run-on experiments. Further, the assessment of GHBP presented a constant, dose-dependent increase, which was completely abolished in the experiments where pegvisomant was used.
Conclusion
We present data showing that growth hormone has a direct impact on GHR/GHPB gene transcription and that pegvisomant is a potent growth hormone receptor antagonist in human mesangial cells. In addition, although the GHR/GHBP gene transcription is down-regulated by supraphysiologic growth hormone concentrations, this effect was not found when GHBP levels were measured. This finding may reflect a self-inhibitory effect of growth hormone on the level of GHR/GHBP gene transcription, which does not involve the regulation of the shedding of GHBP and may, therefore, be of physiologic interest.
Keywords:
growth hormone, growth-hormone-receptor, growth hormone binding protein, transcription, mesangial cells
