Aminoguanidine ameliorates changes in the IGF system in experimental diabetic nephropathy

Background. Formation of advanced glycation endproducts (AGEs) has been imp licated in the development of diabetic complications. As well as causing ch anges in structural proteins, AGEs may also alter gene expression of growth factors in vitro. The insulinlike growth factor (IGF) system, including IG F-I and modulatory IGF binding proteins (IGFBPs), is dysregulated during th e development of diabetic nephropathy. Methods, Quantitative in situ hybridization histochemistry and immunohistoc hemistry were used to determine the effects of aminoguanidine, an inhibitor of AGE formation, on gene expression of IGF-I and IGFBPs in kidneys of lon g-term (8 months duration) streptozotocin-diabetic rats. Results. Diabetes was associated with increased renal expression of IGFBP-1 mRNA (diabetes 824+/-236 vs control 264+/-76 arbitrary units, P<0.01) and decreased expression of mRNAs for IGF-I (diabetes 39+/-7 vs control 185+/-2 3 arbitrary units, P<0.001) and IGFBP-4 (diabetes 139+/-25 vs control 383+/ -54 arbitrary units, P<0.001). Aminoguanidine treatment inhibited the effec ts of diabetes on renal expression of mRNA for IGF-I, IGFBP-1 and IGFBP-4. The changes in IGF-I and IGFBP-1 mRNA levels were reflected in altered pept ide levels. In diabetic kidneys, IGFBP-5 mRNA levels were slightly decrease d to 75% of control levels (P<0.01); aminoguanidine had no effect on IGFBP- 5 mRNA levels. Conclusions. These results suggest that amelioration of changes in the rena l IGF system by aminoguanidine may contribute to the renoprotective effects of the latter, which have been previously shown to inhibit structural and functional aspects of diabetic nephropathy in the rat.