Pre- and post-translational 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 growth retardation in affected animals and humans. This increase in kidney IGF-I gene expression is mediated both by pre- and post-translational mechanisms, with the relative contributions of each locus of control varying with the severity and/or duration of diabetes. Since the actions of IGF-I are modified by specific circulating as well as locally produced IGF binding proteins (IGF BPs), and since kidney IGF BP1 content 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 responsible for this increase in kidney IGF BP1 content.

METHODS

Adult rats were made diabetic by injection of streptozotocin (STZ), and kidney BP1 mRNA and protein were assessed by Northern and Western ligand blotting, respectively, in comparison with nondiabetic, insulin-treated diabetic, and phlorizin-treated diabetic animals.

RESULTS

Rapid time- and STZ dose-dependent increases in both pre- and post-translational renal IGF BP1 expression were noted in the untreated diabetic animals. Comparison of the relative changes in kidney BP1 mRNA and protein contents suggested that with increasing severity of diabetes, at least 20% of this effect was mediated pre-translationally and, therefore, did not merely reflect trapping of circulating BP1. Treatment with insulin completely inhibited the pre-translational and potently inhibited the post-translational component of the response, while correction of hyperglycemia with phlorizin did not. These observations were specific for BP1, with renal IGF BP3 mRNA and protein contents noted to be low basally and unaffected by diabetes.

CONCLUSIONS

These data suggest that insulin strongly regulates pre- and post-translational renal IGF BP1 gene expression and implicate BP1 as an important determinant of IGF-I activity in diabetic kidney. The similarity of the time course of BP1 induction to that of IGF-I in animals of the same age and severity of diabetes suggests that local IGF-I/BP1 interactions may potentiate kidney IGF-I activity and promote initiation of the early stages of diabetic renal hypertrophy.