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

Abstract

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 RAGE in renal changes in type 1 diabetes, we examined the renal effects of a neutralising murine RAGE-antibody (ab) in streptozotocin (STZ)-diabetic mice, a model of type 1 diabetes. One group of STZdiabetic mice was treated for two months with the RAGE-ab, 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-abtreated STZ-diabetic mice, the increase in kidney weight and UAE was reduced, while the increase in CrCl was abolished. RAGE-ab administration in NMRI mice caused a reduction in liver weight and an increase in BMT. Renal messenger RNA (mRNA) for connective tissue growth factor and collagen IV 1 was increased in placebo-treated diabetic animals. RAGE-ab treatment had no impact on 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 pathogenic factor in the renal changes in an animal model of type 1 diabetes.

Mannose-binding lectin deficiency attenuates renal changes in a streptozotocin-induced model of type 1 diabetes in mice

“…Diabetic animals had significantly lower Vegf-A expression than the non-diabetic animals. This is consistent with another study from our group on STZ-diabetic mice killed after 60 days with diabetes [37]. Expression of Vegfr-2 and Nphs1 did not differ between the four groups in the present study.…”

Treatment effect with anti-RAGE F(ab′)2 antibody improves hind limb angiogenesis and blood flow in Type 1 diabetic mice with left femoral artery ligation

“…[20][21][22][23] Blocking or neutralizing antibodies to RAGE have been shown to reduce or ameliorate the detrimental effects of RAGE expression in diabetic renal disease. 24 This is the first study to report a therapeutic effect of a RAGE blocking antibody in limb ischemia. Therapeutic monoclonal antibodies are now approved for clinical use in several diseases, making this approach a possibility to pursue.…”

Advanced glycation end-products induce cell cycle arrest and hypertrophy in podocytes

“…Glomerular AGE accumulation correlates with the severity of diabetic nephropathy [25]. In animal models, neutralisation or scavenging of AGEs prevents podocyte damage [14,26].…”