REDUCTION OF INSULIN-LIKE GROWTH-FACTOR-I (IGF-I) IN PROTEIN-RESTRICTED RATS IS ASSOCIATED WITH DIFFERENTIAL REGULATION OF IGF-BINDING PROTEIN MESSENGER RIBONUCLEIC-ACIDS IN LIVER AND KIDNEY, AND PEPTIDES IN LIVER AND SERUM

To investigate the influence of the insulin-like growth factor binding-proteins (IGFBPs) on the nutritional regulation of IGF-I's actions, we compared the gene expression of IGF-I and the six IGFBPs in liver and kidney of protein-restricted (P5) and normally fed (P15) young rats. Using poly(A)(+) Northern blot analysis, we observed a decrease in IGF-I messenger RNA (mRNA) at steady state in liver (-50%) and kidney (-60%). The increases in IGFBP-1 mRNA were parallel in these two tissues (liver, 5.7-fold; kidney, 4-fold). In contrast, the expression of the other IGFBP genes exhibited organ-specific regulation during protein restriction; although IGFBP-2 mRNA increased in liver in the P5 group (3-fold), it decreased slightly in kidney (-15%). IGFBP-3 mRNA declined by 30% in liver and was unchanged in kidney. IGFBP-4 mRNA increased by 50-88% in liver and was not modified in kidney. IGFBP-5 mRNA was not detected in liver and was identical in kidney of P15 and P5 rats. IGFBP-6 mRNA was not changed in either liver or kidney during protein restriction. To determine whether the changes in IGFBP mRNAs induced by protein restriction were associated with changes in the respective peptides, IGFBPs in supernatants of liver homogenates and in serum of the same rats were measured by ligand blot analyses. IGFBP-1 and IGFBP-2 Western immunoblot analyses were also performed in serum. By ligand blot, a 45,000 mol wt (M(r)) band (IGFBP-3) decreased in liver and serum of P5 rats, paralleling the changes in liver IGFBP-3 mRNA. A 30,000 M(r) band, consistent with IGFBP-1 and/or IGFBP-2, increased in liver. By immunoblot in serum, IGFBP-1 was only detectable in P5 rats, whereas IGFBP-2 decreased in the P5 group. By ligand blot, a 24,000 M(r) band (IGFBP-4) declined slightly in serum (not detected in liver). Our study shows that protein restriction regulates the expression of four of six IGFBPs in rats, and this regulation is organ specific. The nutritional regulation of IGFBP peptides in biological fluids, in particular serum, seems to involve additional mechanisms.