Laboratory Investigation

Kidney International (1994) 45, 1085–1092; doi:10.1038/ki.1994.145

Reduced hepatic growth hormone (GH) receptor gene expression and increased plasma GH binding protein in experimental uremia

Burkhard Tönshoff, Staffan Edén, Eckart Weiser, Björn Carlsson, Iain C A F Robinson, Werner F Blum and Otto Mehls

Division of Pediatric Nephrology, University Children's Hospital, Heidelberg, Germany; Department of Physiology, University of Göteborg, Sweden; National Institute for Medical Research, London, England, United Kingdom; and University Children's Hospital, Tübingen, Germany

Correspondence: Burkhard Tönshoff MD, Division of Pediatric Nephrology, Department of Pediatrics, School of Medicine, State University of New York at Stony Brook, Stony Brook, New York 11794-8111, USA.

Received 25 August 1993; Revised 5 November 1993; Accepted 8 November 1993.

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Abstract

Reduced hepatic growth hormone (GH) receptor gene expression and increased plasma GH binding protein in experimental uremia. In uremia, reduced longitudinal growth and decreased hepatic insulin-like growth factor-I (IGF-I) secretion despite elevated GH serum levels point to an insensitivity to the action of GH. The molecular basis that accounts for this insensitivity could comprise decreased GH receptor expression in the target organs for GH or binding of GH in the circulation to substances that compete with the receptor. To address this hypothesis, the abundance of hepatic GH receptor mRNA was measured by solution hybridization RNase protection assay in uremic female Spra-gue-Dawley rats, following two-stage 5/6 nephrectomy, and in pair-fed and in ad libitum-ted sham-operated controls; rat GH binding protein (GHBP) plasma concentration was measured by a sensitive direct RIA. Uremia was associated with a 50% decrease of hepatic GH receptor expression compared to pair-fed controls, which themselves showed a 25% reduction of hepatic GH receptor mRNA abundance when compared to ad libitum-ted controls. Plasma GHBP levels in uremia were markedly higher than in both control groups. Treatment with recombinant human GH (rhGH) (10 IU/kg body wt per day s.c. for 10 days) led to a comparable induction of IGF-I plasma levels and weight gain in uremia and pair-fed controls, indicating that the insensitivity to GH in uremia can be overcome by large rhGH doses. Subcutaneous rhGH injections did not significantly alter the hepatic GH receptor transcript abundance or plasma GHBP levels in any of the groups. Methylprednisolone (6 mg/kg body wt per day given for 10 days) significantly suppressed weight gain and food conversion ratio in all experimental groups, accompanied by a 50% reduction of plasma GHBP, but without a consistent effect on hepatic GH receptor mRNA abundance or circulating IGF-I. This study demonstrates that experimental uremia in rats leads to a decreased expression of hepatic GH receptor mRNA. This decrease is partly due to a reduced nutritional intake but also involves other as yet unidentified mechanisms. Circulating GHBP is increased in the uremic state and could potentially compete for ligand binding to the receptor. We hypothesize that both these alterations contribute to GH insensitivity in uremia.

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