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Amelioration of long-term renal changes in obese type 2 diabetic mice by a neutralizing vascular endothelial growth
Allan Flyvbjerg1, Frederik Dagnaes-Hansen, An S De Vriese
1Medical Department M and Medical Research Laboratories, Institute of Experimental Clinical Research, Aarhus University Hospital, Denmark. allan.flyvbjerg@dadlnet.dk
Abstract:
Diabetic nephropathy in type 2 diabetic patients is a frequent complication associated with increased morbidity and mortality. Various growth factors and cytokines have been implicated in the pathogenesis of diabetic kidney disease, including vascular endothelial growth factor (VEGF). To explore a role for VEGF in renal changes in type 2 diabetes, we examined the renal effects of a neutralizing murine VEGF antibody in the diabetic db/db mouse, a model of obese type 2 diabetes. One group of db/db mice was treated for 2 months with a VEGF antibody, while another db/db group was treated for the same period with an isotype-matched irrelevant IgG. A third group consisting of nondiabetic db/+ mice was treated with the same 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 (CrCl) when compared with nondiabetic controls. In VEGF antibody-treated db/db mice, increases in kidney weight, glomerular volume, BMT, and UAE were attenuated, whereas the increase in CrCl was abolished. VEGF antibody administration tended to reduce expansion in total mesangial volume. These effects in diabetic animals were seen without impact on body weight, blood glucose, insulin levels, or food consumption. In conclusion, chronic inhibition of VEGF in db/db mice ameliorates the diabetic renal changes seen in type 2 diabetes.
Insights
Vascular Endothelial Growth Factor (VEGF) inhibition improves kidney complications in type 2 diabetes. Neutralizing VEGF in diabetic mice reduced kidney weight, glomerular volume, and albuminuria without affecting blood glucose.
Area of Science:
- Nephrology
- Endocrinology
- Molecular Biology
Background:
- Diabetic nephropathy is a major complication of type 2 diabetes, increasing morbidity and mortality.
- Vascular Endothelial Growth Factor (VEGF) is implicated in the pathogenesis of diabetic kidney disease.
Purpose of the Study:
- To investigate the role of VEGF in the renal complications of type 2 diabetes.
- To examine the effects of a neutralizing VEGF antibody on diabetic kidney disease in a mouse model.
Main Methods:
- Diabetic db/db mice and non-diabetic db/+ mice were treated with either a VEGF antibody or an isotype-matched IgG for two months.
- Renal changes including kidney weight, glomerular volume, basement membrane thickness, mesangial volume, urinary albumin excretion, and creatinine clearance were assessed.
Main Results:
- Diabetic mice showed increased kidney weight, glomerular volume, basement membrane thickness, and albuminuria compared to controls.
- VEGF antibody treatment attenuated these renal changes and abolished the increase in creatinine clearance.
- These improvements occurred without affecting body weight, blood glucose, or insulin levels.
Conclusions:
- Chronic inhibition of VEGF ameliorates key renal changes associated with type 2 diabetic nephropathy.
- VEGF plays a significant role in the development of diabetic kidney disease.
- Targeting VEGF may be a potential therapeutic strategy for diabetic nephropathy.
