Renal effects of a neutralising RAGE-antibody in long-term streptozotocin-diabetic mice.
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.
Jensen
Louise J N
LJ
Medical Department M and Medical Research Laboratories, Clinical Institute, Aarhus University Hospital, DK-8000 Aarhus C, Denmark.
Denner
Larry
L
Schrijvers
Bieke F
BF
Tilton
Ronald G
RG
Rasch
Ruth
R
Flyvbjerg
Allan
A
D000419:Albuminuria; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001786:Blood Glucose / Q000032:analysis; D024141:Collagen Type IV / Q000235:genetics; D055513:Connective Tissue Growth Factor; D003404:Creatinine / Q000652:urine; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005260:Female; D017874:Immediate-Early Proteins / Q000235:genetics; D007074:Immunoglobulin G / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008657:Metabolic Clearance Rate / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D000911:Antibodies, Monoclonal; D001786:Blood Glucose; C526318:CCN2 protein, mouse; D024141:Collagen Type IV; D017874:Immediate-Early Proteins; D007074:Immunoglobulin G; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D055513:Connective Tissue Growth Factor; D003404:Creatinine