Renal effects of a neutralising RAGE-antibody in long-term streptozotocin-diabetic mice

Advanced glycation endproducts (AGEs) have been implicated in the pathogenesis of diabetic kidney disease. The actions of AGEs are mediated both through a non-receptor mediated pathway and through specific receptors for AGEs (e.g. RAGE). To explore a potentially specific role for R-AGE in renal changes in type I diabetes, we examined the renal effects of a neutralising murine P,AGE-antibody (ab) in streptozotocin (STZ)-diabetic mice, a model of type 1 diabetes. One group of STZ-diabetic mice was treated for two months with the RAGE, while another STZ-diabetic group was treated for the same period with an irrelevant immunoglobulin G (IgG). Two groups of non-diabetic NMRI mice were treated with either RAGE-ab or isotype-matched IgG for two months. Placebo-treated STZ-diabetic mice showed an increase in kidney weight, glomerular volume, basement membrane thickness (BMT), urinary albumin excretion (UAE) and creatinine clearance (CrCl), when compared with non-diabetic controls. In RAGE-ab-treated STZ-diabetic mice, the increase in kidney weight and UAE was reduced, while the increase in CrCl,vas abolished. RAGE-ab administration in NMRI mice Caused a reduction in liver weight and all increase in BMT. Renal messenger RNA (mRNA) for connective tissue growth factor and collagen IV alpha 1 was increased in placebo-treated diabetic animals. RAGE-ab treatment had no impact oil the expression of these factors. The renal effects of RAGE-ab administration in STZ-diabetic mice were seen without impact on body weight, blood glucose or food consumption. In conclusion, the present data Support the hypothesis that RAGE is an important pathogellic factor in the renal changes in all animal model of type 1 diabetes.