Stimulating Effect of Recombinant Human Erythropoietin (rhEPO) on Insulin-like Growth Factor-I (IGF-I) Production by Hepatocytes in Rats with or without Subtotal Nephrectomy

S We investigated the effect of recombinant human erythropoietin (rhEPO) on insulin-like growth factor-I (IGF-I) production in primary cultured rat hepatocytes. Hepatocytes were obtained by in situ collagenase perfusion from adult male Wistar rats with sham-operation (control rats) or 5/6 nephrectomy (chRF rats), in which renal function was impaired and associated with renal anemia 4 weeks after the surgery. The hepatocytes were cultured at a density of 5 X 10 5 cells/mL in Williams' medium E with different doses of rhEPO for 48 h. IGF-I concentrations were measured by specific radioimmunoassay after acid-ethanol extraction. Plasma EPO levels were lower in chRF rats than in control rats at 4 weeks after the surgery (1.8′0.1 vs 2.6′0.3 mU/mL, P<0.05), whereas plasma IGF-I levels were rather higher in chRF rats (778.3 ′53.5 vs 636.0′70.0, P<0.05). Medium IGF-I levels were not different between the two groups (control rats 9.8′1.7 ng/mL vs chRF rats 10.1′ 1.8 ng/mL) and were dose-dependently increased by rhEPO (10 - 1 1 -10 - 8 M) in both groups of animals. An increment of medium IGF-I after the incubation with 10 - 8 M rhEPO for 48 h was 5 fold greater in control rats than in chRF rats (Δ13.6′3.9 vs Δ2.7′1.5 ng/mL, P<0.05). These findings suggest that EPO directly stimulates IGF-I release from rat hepatocytes and that the stimulating effect of EPO is blunted in chRF rats.