DECREASED HEPATIC INSULIN-LIKE GROWTH-FACTOR (IGF)-I AND INCREASED IGF BINDING PROTEIN-1 AND PROTEIN-2 GENE-EXPRESSION IN EXPERIMENTAL UREMIA

The imbalance between normal insulin-like growth factor-I (IGF-I) and markedly increased IGF binding protein (IGFBP) plasma levels plays a p athogenic role for growth retardation and catabolism in children with chronic renal failure. To investigate the mechanism of these alteratio ns, experiments were performed in an experimental model of uremia in r ats (5/6 nephrectomy) and in pair-fed and ad libitum-fed sham-operated controls. Using a specific solution hybridization/RNase protection as say, we observed a marked reduction of hepatic IGF-I messenger RNA (mR NA) abundance at steady state in uremic animals (37+/-5% of control) c ompared both with pair-fed (65+/-10%) and ad libitum-fed controls (100 =11%) (P <0.001). Reduced IGF-I gene expression was clearly organ-spec ific; it was most pronounced in liver (significant vs.. pair-fed contr ols) and lung and muscle tissue (significant vs.. ad libitum-fed contr ols); no change was observed in kidney and heart tissue. To determine a potential mechanism of reduced hepatic IGF-I gene expression in urem ia, the hepatic GH receptor gene expression in the same experimental a nimals was analyzed by specific solution hybridization/RNase protectio n assay. Uremic animals had a 20-30% reduction of hepatic GH receptor mRNA abundance compared with controls. Hepatic GHBP expression in urem ia was decreased in parallel. Despite the reduction of hepatic IGF-I m RNA abundance, plasma IGF-I levels in uremia were not different from a d libitum-fed controls. This discrepancy is explained by an increased concentration of IGFBPs in uremic plasma. By RIA, plasma IGFBP-1 level s in uremia were increased 4-fold; by Western immunoblot, plasma IGFBF -2 levels were increased 7-fold and plasma IGFBP-4 levels were increas ed 2-fold compared with both control groups. Intact IGFBP-3 (M(r), sim ilar to 48 kDa) and low molecular IGFBP-3 fragments mere not significa ntly different among the three groups. By Northern blot analysis, hepa tic IGFBP-1 mRNA levels in uremia were 2-fold higher than in controls. IGFBP-2 mRNA abundance in Liver tissue was increased 4-fold, whereas in kidney there was a significant reduction of IGFBP-2 mRNA (30% of co ntrol). IGFBP-4 mRNA was increased by 50% in kidney but not in liver. Plasma insulin and corticosterone levels were not different among the groups. Our study shows that hepatic IGF-I gene expression was specifi cally reduced in uremia, partially as the consequence of a reduced hep atic GH receptor gene expression. One of the mechanisms contributing t o increased IGFBP levels in uremia is increased hepatic gene expressio n of IGFBP-1 and IGFBP-5. The imbalance between reduced hepatic TGF-I production and increased hepatic IGFBP-1 and -2 production is likely t o play a pathogenic role for catabolism and growth failure in CRF.