Studies on the renal kinetics of growth hormone (GH) and on the GH receptor and related effects in animals.
Growth hormone (GH) is filtered through the kidney, and may exert effects on renal function when presented via the circulation. Investigations on kidney-related aspects of GH are increasing in number. Using in vitro and in vivo approaches, the present study attempted to provide answers to a number of unresolved or debated issues. In vitro, we detected both GH and type 1 IGF receptors (R) in a porcine renal epithelial cell line. The saturation and down regulation kinetics of the GH-R indicate that it has the properties of a classical GH-R. Furthermore, the simultaneous presence of GH-R and IGF-R on a phenotypically homogeneous cell line suggests the presence of GH-induced auto-/paracrine IGF-1 bioactivity in the kidney. Experiments with isolated proximal rabbit tubules incubated with physiological concentrations of 125I-GH demonstrated a time-and dose-dependent increase in unlabelled GH-displaceable cell-associated radioactivity, lending support to the concept of GH mediating its renal effects via proximal tubular GH-R. Short term administration of GH to rats and humans elicited electrolyte and water retention that may cause edema in adults. In the present study, long term administration of GH to rats caused only a minor increase in serum phosphate levels, with no changes observed in the renal electrolyte clearance. During the first 4 days of GH treatment in rats, no change in plasma renin activity was detected and we were thus unable to confirm the hypothesis that the renin-angiotensin system is responsible for the early phase of GH-associated fluid retention. Pharmacokinetically, when GH was administered to rats with functional disconnection of the kidneys as a model of renal insufficiency, the whole body clearance of GH decreased by ca. two thirds, and was reflected by an increase in the mean residence time and AUCplasma for GH. The plasma half-life, however, was not significantly affected, suggesting that the volume of distribution (Vd) had decreased for the GH administered to the renally compromised animals. A renal contribution to the Vd was visualized as intense radioactive staining in the kidney region on whole body autoradiographs (WBA) of rats dosed with 125I-labelled hGH. The liver region was also intensely stained. Kidney-associated radioactivity was found to be related not only to glomerular filtration, but also to peritubular uptake, since the renal clearance of free GH was found to exceed the GFR.(ABSTRACT TRUNCATED AT 400 WORDS)
Krogsgaard Thomsen
M
M
Biopharmaceuticals Division, Research and Development, Novo Nordisk A/S, Gentofte, Denmark.
Friis
C
C
Sehested Hansen
B
B
Johansen
P
P
Eschen
C
C
Nowak
J
J
Poulsen
K
K
D000818:Animals; D001345:Autoradiography; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D004573:Electrolytes / Q000378:metabolism; D005260:Female; D013006:Growth Hormone / Q000493:pharmacokinetics* / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D007668:Kidney / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D010052:Ovariectomy; D011817:Rabbits; D051381:Rats; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000378:metabolism*; D012083:Renin / Q000097:blood; D013552:Swine
D004573:Electrolytes; D007457:Iodine Radioisotopes; D017527:Receptor, IGF Type 2; D011986:Receptors, Somatotropin; D013006:Growth Hormone; D012083:Renin