Long-term renal effects of a neutralizing RAGE antibody in obese type 2 diabetic mice.
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.
Flyvbjerg
Allan
A
Medical Department M and Medical Research Laboratories, Institute of Experimental Clinical Research, Aarhus University Hospital, Aarhus, Denmark. allan.flyvbjerg@dadlnet.dk
Denner
Larry
L
Schrijvers
Bieke F
BF
Tilton
Ronald G
RG
Mogensen
Trine H
TH
Paludan
Søren R
SR
Rasch
Ruth
R
D000419:Albuminuria / Q000276:immunology / Q000517:prevention & control; D000818:Animals; D000906:Antibodies / Q000097:blood* / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D003404:Creatinine / Q000378:metabolism; D003920:Diabetes Mellitus / Q000097:blood / Q000276:immunology*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000276:immunology*; D017127:Glycation End Products, Advanced; D007668:Kidney / Q000201:enzymology / Q000503:physiopathology; D051379:Mice; D008817:Mice, Mutant Strains; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009765:Obesity; D009929:Organ Size; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000276:immunology*
D000906:Antibodies; D001786:Blood Glucose; D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D003404:Creatinine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse