PRE- AND POSTTRANSLATIONAL REGULATION OF RENAL INSULIN-LIKE GROWTH-FACTOR BINDING PROTEIN-1 IN INSULIN-DEFICIENT DIABETES

Background: Renal size and production of insulin-like growth factor-I (IGF-I) increase rapidly after the onset of insulin-deficient diabetes , despite decreases in serum and hepatic levels of IGF-I and linear gr owth retardation in affected animals and humans. This increase in kidn ey IGF-I gene expression is mediated both by pre- and post-translation al mechanisms, with the relative contributions of each locus of contro l varying with the severity and/or duration of diabetes. Since the act ions of IGF-I are modified by specific circulating as well as locally produced IGF binding proteins (IGF BPs), and since kidney IGF BP1 cont ent is increased in diabetes, we asked whether: 1) the time course of induction of increased BP1 expression paralleled that for induction of IGF-I; 2) severity and/or duration of diabetes affected pre- and post -translational renal expression of this protein as it does expression of IGF-I itself; and 3) insulin deficiency or hyperglycemia was respon sible for this increase in kidney IGF BP1 content. Methods: Adult rats were made diabetic by injection of streptozotocin (STZ), and kidney B P1 mRNA and protein were assessed by Northern and Western ligand blott ing, respectively, in comparison,vith nondiabetic, insulin-treated dia betic, and phlorizin-treated diabetic animals. Results: Rapid time- an d STZ dose-dependent increases in both pre- and post-translational ren al IGF BP1 expression were noted in the untreated diabetic animals. Co mparison of the relative changes in kidney BP1 mRNA and protein conten ts suggested that with increasing severity of diabetes, at least 20% o f this effect was mediated pretranslationally and, therefore, did not merely reflect trapping of circulating BP1. Treatment with insulin com pletely inhibited the pre-translational and potently inhibited the pos t-translational component of the response, while correction of hypergl ycemia with phlorizin did not. These observations were specific for BP 1, with renal IGF BP3 mRNA and protein contents noted to be low basall y and unaffected by diabetes. Conclusions: These data suggest that ins ulin strongly regulates pre- and post-translational renal IGF BP1 gene expression and implicate BP1 as an important determinant of IGF-I act ivity in diabetic kidney. The similarity of the time course of BP1 ind uction to that of IGF-I in animals of the same age and severity of dia betes suggests that local IGF-I/BP1 interactions may potentiate kidney IGF-I activity and promote initiation of the early stages of diabetic renal hypertrophy.