Faculty Bibliography

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

Pubertal mammary development in the rat is largely dependent upon GH and estrogen. We recently showed that insulin-like growth factor-I (IGF-I) can substitute for GH in inducing mammary development in male rats, suggesting that IGF-I mediates GH action. The present study investigated whether IGF-I, like GH, required estradiol (E2) to act or whether IGF-I could substitute for both GH and E2. The effects of IGF-I were tested in the presence and absence of E2. Elvax pellets containing IGF-I or des(1-3) IGF-I were implanted into right lumbar mammary glands of sexually immature, hypophysectomized, oophorectomized female rats, with control BSA-containing pellets in the contralateral glands. After 5 days, both lumbar mammary glands were removed and examined in whole mounts for mammary development by counting terminal end buds and alveolar structures. E2, administered in SILASTIC brand capsules, had no independent effect on mammary development. In the absence of E2, des(1-3) IGF-I had a small, but significant, independent effect on mammary development; native IGF-I was ineffective. The addition of E2 significantly enhanced the effects of IGF-I and des(1-3) IGF-I on mammary development, similar to that noted when E2 was given along with GH. We also studied the effects of E2 and/or hGH on mammary gland IGF-I messenger RNA (mRNA) in hypophysectomized castrated male animals. E2 alone did not increase mammary gland IGF-I mRNA concentrations, but E2 enhanced the effect of hGH on IGF-I mRNA by 4- to 6-fold. These studies indicate that IGF-I can have a small independent effect on mammary development, but like GH, E2 is required for a full effect. They also indicate that E2 is capable of synergizing with GH in the production or expression of IGF-I mRNA, and that the action of E2 on mammary development may take place at multiple sites. If locally produced IGF-I does indeed mediate the action of GH in mammary development, then although E2 is capable of enhancing the effect of GH on IGF-I mRNA, its major effect in mammary development occurs after IGF-I is produced

BACKGROUND: Left ventricular hypertrophy is a generalized adaptation to increased afterload, but the growth factors mediating this response have not been identified. To explore whether the hypertrophic response was associated with changes in local insulin-like growth factor-I (IGF-I) gene regulation, we examined the induction of the cardiac IGF-I gene in three models of systolic hypertension and resultant hypertrophy. METHODS AND RESULTS: The model systems were suprarenal aortic constriction, uninephrectomized spontaneously hypertensive rats (SHR), and uninephrectomized, deoxycorticosterone-treated, saline-fed rats (DOCA salt). Systolic blood pressure reached hypertensive levels at 3 to 4 weeks in all three systems. A differential increase in ventricular weight to body weight (hypertrophy) occurred at 3 weeks in the SHR and aortic constriction models and at 4 weeks in the DOCA salt model. Ventricular IGF-I mRNA was detected by solution hybridization/RNase protection assay. IGF-I mRNA levels increased in all three systems coincident with the onset of hypertension and the development of ventricular hypertrophy. Maximum induction was 10-fold over control at 5 weeks in the aortic constriction model, 8-fold at 3 weeks in the SHR, and 6-fold at 6 weeks in the DOCA salt model. IGF-I mRNA levels returned to control values by the end of the experimental period despite continued hypertension and hypertrophy in all three systems. In contrast, ventricular c-myc mRNA content increased twofold to threefold at 1 week and returned to control levels by 2 weeks. Ventricular IGF-I receptor mRNA levels were unchanged over the time course studied. The increased ventricular IGF-I mRNA content was reflected in an increased ventricular IGF-I protein content, as determined both by radioimmunoassay and immunofluorescence histochemistry. CONCLUSIONS: We conclude that (1) hypertension induces significant increases in cardiac IGF-I mRNA and protein that occur coordinately with its onset and early in the development of hypertrophy, (2) IGF-I mRNA levels normalize as the hypertrophic response is established, (3) in comparison to IGF-I, both c-myc and IGF-I receptor genes are differentially controlled in experimental hypertension. These findings suggest that IGF-I may participate in initiating ventricular hypertrophy in response to altered loading conditions. The consistency of these findings in models of high-, moderate-, and low-renin hypertension suggests that they occur independently of the systemic renin-angiotensin endocrine axis