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Renal effects of a neutralising RAGE-antibody in long-term streptozotocin-diabetic mice
Louise J N Jensen1, Larry Denner, Bieke F Schrijvers
1Medical Department M and Medical Research Laboratories, Clinical Institute, Aarhus University Hospital, DK-8000 Aarhus C, Denmark.
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 STZ-diabetic 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-ab-treated 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 IValpha1 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.
Insights
Advanced glycation endproducts (AGEs) contribute to diabetic kidney disease. Targeting the Receptor for AGEs (RAGE) with an antibody in a type 1 diabetes mouse model reduced kidney damage, suggesting RAGE is a key factor.
Area of Science:
- Nephrology
- Endocrinology
- Immunology
Background:
- Advanced glycation endproducts (AGEs) are implicated in diabetic kidney disease pathogenesis.
- AGEs exert effects via non-receptor mediated pathways and specific receptors like RAGE.
- The role of RAGE in type 1 diabetic nephropathy requires further investigation.
Purpose of the Study:
- To investigate the specific role of RAGE in renal alterations observed in type 1 diabetes.
- To evaluate the therapeutic potential of a neutralizing RAGE-antibody in a mouse model of type 1 diabetes.
Main Methods:
- Streptozotocin (STZ)-induced diabetic mice and non-diabetic controls were used.
- Mice were treated with a RAGE-antibody or an irrelevant IgG for two months.
- Renal function, kidney weight, glomerular parameters, and specific gene expression were assessed.
Main Results:
- STZ-diabetic mice exhibited increased kidney weight, glomerular volume, basement membrane thickness, urinary albumin excretion (UAE), and creatinine clearance (CrCl).
- RAGE-antibody treatment significantly reduced kidney weight and UAE, and abolished the increase in CrCl in diabetic mice.
- RAGE-antibody treatment did not affect body weight, blood glucose, or food consumption in diabetic mice.
Conclusions:
- RAGE is a significant pathogenic factor in the renal complications of type 1 diabetes.
- Neutralizing RAGE with an antibody demonstrates a protective effect on kidney structure and function in this model.
- Targeting RAGE may represent a potential therapeutic strategy for diabetic kidney disease.
