Regional changes in the intrarenal insulin-like growth factor-I axis in diabetes

Abstract

Since insulin-like growth factor-I (IGF-I) has been shown to promote renal growth and as kidney IGF-I content increases during the early days after the onset of diabetes, it is likely that this growth factor contributes to initial diabetic renal hypertrophy. However, it is unclear whether IGF-I contributes to the continued renal growth that occurs in diabetes. Since IGF-I action is mediated through its receptor and as its bioavailability is regulated by IGF binding proteins (IGFBP), we postulated that changes in IGF-I receptor binding or IGFBP production may favor a role for IGF-I in diabetic renal growth when kidney IGF-I levels have returned to normal. To test this thesis, we studied kidneys of rats after seven days of streptozotocin diabetes. In diabetic cortex and medulla, growth hormone receptor mRNA levels and IGF-I and IGF-I receptor mRNA and protein product levels were unchanged. In cortex IGFBP-1 mRNA levels were increased while IGFBP-2 and -4 mRNA levels decreased. In medulla the only change was a fall in IGFBP-1 mRNA levels. Using Western ligand blot we observed an increase in a 32 kDa plasma membrane-associated IGFBP. Insulin therapy reversed all changes except the elevated cortical IGFBP-1 mRNA levels, indicating the presence of regional heterogeneity in the IGFBP response to diabetes in the kidney. However, the lack of change in IGF-I, IGF-I receptor and growth hormone receptor gene expression and protein products after one week of diabetes argues against a role for IGF-I in sustaining diabetic renal growth beyond the initial growth phase.