EXPRESSION OF INSULIN-LIKE GROWTH-FACTOR BINDING-PROTEINS IN THE RAT-KIDNEY - EFFECTS OF LONG-TERM DIABETES

Recent studies have shown that the renal synthesis of insulin-like gro wth factor binding proteins (IGFBPs) is altered in insulin-deficient d iabetes mellitus, suggesting that these changes may be implicated in t he alterations in renal function and morphology that accompany diabete s. To investigate the time course and the precise cellular distributio n of changes in IGFBP expression, we used quantitative in situ hybridi zation to analyze renal IGF-I and IGFBP-1 to -5 messenger RNA (mRNA)lo calization and levels from 2 days to 6 months after the onset of strep tozotocin-induced diabetes. There was an immediate sharp decline in IG F-I mRNA levels in the outer medulla that persisted for up to 3 months and a much smaller reduction in IGF-I mRNA levels in the medullary th ick ascending limbs (MTALs). In nondiabetic animals, IGFBP-1 mRNA is m ost abundant in the MTALs. Immediately after the induction of diabetes , however, there was a greater than a-fold increase in cortical IGFBP- 1 mRNA and a 75% decrease in IGFBP-1 mRNA in MTALs. These changes pers isted for up to 6 months in the diabetic animals. In contrast, IGFBP-5 mRNA levels were increased in the outer medulla and decreased in the cortex of diabetic kidneys. No significant changes in renal IGFBP-2 mR NA level or distribution were noted, and changes in IGFBP-3 and -4 mRN A levels were subtle. In summary, streptozotocin-induced diabetes is a ssociated with very prominent and complex alterations in renal IGF sys tem gene expression, including robust increases in cortical IGFBP-1 an d profound decreases in cortical IGFBP-5 mRNA and medullary IGF-I mRNA levels. The divergent changes in IGFBP-1 and -5 mRNA levels in cortex vs. outer medulla indicate that regulation of IGFBP mRNA levels is qu ite complex.