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Long-term renal effects of a neutralizing RAGE antibody in obese type 2 diabetic mice
Allan Flyvbjerg1, Larry Denner, Bieke F Schrijvers
1Medical Department M and Medical Research Laboratories, Institute of Experimental Clinical Research, Aarhus University Hospital, Aarhus, Denmark. allan.flyvbjerg@dadlnet.dk
Abstract:
Advanced glycation end products (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 AGE (RAGEs). To explore a specific role for RAGE in renal changes in type 2 diabetes, we examined the renal effects of a neutralizing murine RAGE antibody in db/db mice, a model of obese type 2 diabetes. One group of db/db mice was treated for 2 months with the RAGE antibody, and another db/db group was treated for the same period with an irrelevant IgG. Two groups of nondiabetic db/+ mice were treated with either RAGE antibody or isotype-matched IgG for 2 months. Placebo-treated db/db mice showed a pronounced increase in kidney weight, glomerular volume, basement membrane thickness (BMT), total mesangial volume, urinary albumin excretion (UAE), and creatinine clearance compared with nondiabetic controls. In RAGE antibody-treated db/db mice, the increase in kidney weight, glomerular volume, mesangial volume, and UAE was reduced, whereas the increase in creatinine clearance and BMT was fully normalized. Notably, these effects in db/db mice were seen without impact on body weight, blood glucose, insulin levels, or food consumption. In conclusion, RAGE is an important pathogenetic factor in the renal changes in an animal model of type 2 diabetes.
Insights
Blocking the receptor for Advanced Glycation End products (RAGE) with an antibody improved kidney function and reduced damage in a type 2 diabetes mouse model. This highlights RAGE as a key factor in diabetic kidney disease.
Area of Science:
- Nephrology
- Endocrinology
- Immunology
Background:
- Advanced glycation end products (AGEs) contribute to diabetic kidney disease pathogenesis.
- AGEs exert effects via non-receptor pathways and specific receptors, including RAGE.
- The role of RAGE in diabetic nephropathy requires further elucidation.
Purpose of the Study:
- To investigate the specific role of RAGE in renal alterations associated with type 2 diabetes.
- To evaluate the therapeutic potential of neutralizing RAGE activity in a diabetic kidney disease model.
Main Methods:
- Utilized db/db mice, a model for obese type 2 diabetes.
- Administered a neutralizing murine RAGE antibody or an irrelevant IgG control for 2 months.
- Included nondiabetic db/+ mice treated with RAGE antibody or IgG as controls.
- Assessed kidney weight, glomerular volume, basement membrane thickness (BMT), mesangial volume, urinary albumin excretion (UAE), and creatinine clearance.
Main Results:
- db/db mice showed increased kidney weight, glomerular volume, BMT, mesangial volume, UAE, and creatinine clearance compared to controls.
- RAGE antibody treatment in db/db mice reduced kidney weight, glomerular volume, mesangial volume, and UAE.
- Creatinine clearance and BMT were normalized in RAGE antibody-treated db/db mice.
- No significant impact on body weight, blood glucose, insulin levels, or food consumption was observed.
Conclusions:
- Receptor for Advanced Glycation End products (RAGE) plays a significant role in the renal pathology of type 2 diabetes.
- Neutralizing RAGE activity offers a potential therapeutic strategy for mitigating diabetic kidney disease progression.
- Targeting RAGE may be effective without altering systemic metabolic parameters.
