Aminoguanidine ameliorates changes in the IGF system in experimental diabetic nephropathy.
BACKGROUND
Formation of advanced glycation end-products (AGEs) has been implicated in the development of diabetic complications. As well as causing changes in structural proteins, AGEs may also alter gene expression of growth factors in vitro. The insulin-like growth factor (IGF) system, including IGF-I and modulatory IGF binding proteins (IGFBPs), is dysregulated during the development of diabetic nephropathy.


METHODS
Quantitative in situ hybridization histochemistry and immunohistochemistry were used to determine the effects of aminoguanidine, an inhibitor of AGE formation, on gene expression of IGF-I and IGFBPs in kidneys of long-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+/-23 arbitrary units, P<0.001) and IGFBP-4 (diabetes 139+/-25 vs control 383+/-54 arbitrary units, P<0.001). Aminoguanidine treatment inhibited the effects 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 peptide levels. In diabetic kidneys, IGFBP-5 mRNA levels were slightly decreased 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 renal 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.
Bach
L A
LA
University of Melbourne, Department of Medicine, Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia.
Dean
R
R
Youssef
S
S
Cooper
M E
ME
D000818:Animals; D003928:Diabetic Nephropathies / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors; D006146:Guanidines / Q000494:pharmacology*; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000378:metabolism; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000378:metabolism; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000235:genetics; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D017127:Glycation End Products, Advanced; D006146:Guanidines; D018970:Insulin-Like Growth Factor Binding Protein 1; D018974:Insulin-Like Growth Factor Binding Protein 4; D018975:Insulin-Like Growth Factor Binding Protein 5; D018969:Insulin-Like Growth Factor Binding Proteins; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; C004479:pimagedine