INSULIN-LIKE GROWTH-FACTOR-I AND ITS BINDING-PROTEINS IN THE EXPERIMENTAL NEPHROTIC SYNDROME

Insulin-like growth factor I (IGF-I) is present in serum in associatio n with specific IGF-binding proteins (IGFBPs) primarily in a large (si milar to 150K) ternary or a smaller (similar to 50K) binary protein co mplex or in the free form (less than or equal to 1%). We hypothesized that glomerular proteinuria results in urinary excretion of IGF-I/IGF- binding protein complexes and that the nephrotic syndrome induces abno rmal serum distribution and liver synthesis of IGF-binding proteins. I n nephrotic rats, serum IGF-I levels are reduced compared with pair-fe d control animals. In nephrotic rat serum, binding to IGFBP-3 is reduc ed and Western immune analysis demonstrates an approximately 27K fragm ent that does not bind IGF-I, suggesting in vivo proteolysis of IGFBP- 3. In contrast, binding and serum levels of IGFBP-2 are increased in n ephrotic rats, which results from increased synthesis in the liver. In Nagase analbuminemic rats, the IGF-I levels and IGFBP-distribution in serum are normal suggesting that the reduced albumin levels in the ne phrotic syndrome do not cause the increased liver synthesis and serum levels of IGFBP-2. Nephrotic rat urine contains IGFBP-3 and IGFBP-2 as well as strong activity of an IGFBP-3 protease. Because the 150K tern ary complex in serum but not the smaller binding protein complex is re stricted to the intravascular space, the shift of binding from IGFBP-3 (ternary complex) to IGFBP-2 (binary complex) in nephrotic rat serum may help to maintain tissue availability despite the reduction in seru m IGF-I levels.