Amelioration of diabetic nephropathy by treatment with monoclonal antibodies against glycated albumin.
The pathogenesis of diabetic nephropathy is incompletely understood, but increased nonenzymatic glycation of proteins is considered an important contributory factor. Glycated albumin, which is increased in diabetic sera and is preferentially transported into the renal glomerulus, induces an increase in Type IV collagen production and a decrease in proliferative capacity by mesangial cells in culture. These effects resemble the abnormalities that characterize the glomerular mesangium in diabetes and are prevented by monoclonal antibodies that specifically react with Amadori adducts in glycated albumin. To explore the possibility that the in vitro effects of glycated albumin on mesangial cell biology pertain to the in vivo situation, we examined the effect of treatment with the A717 monoclonal antibodies on glomerular functional and structural changes in a rodent model of genetic diabetes, the db/db mouse. Weekly parenteral antibody administration reduced the elevated albumin excretion and attenuated the mesangial expansion that were observed in the untreated db/db mice that served as controls. Monoclonal antibody treatment also was shown to lower plasma concentrations of glycated albumin in diabetic mice. Thus, reducing glycated albumin concentrations and/or blocking its biologically active epitopes has a salutary influence on the pathogenesis of diabetic nephropathy. The findings indicate that glycated albumin participates in the development of the glomerular lesion in the db/db mouse, and suggest a new approach to the therapy of this complication of diabetes.
Cohen
M P
MP
University City Science Center, University of Pennsylvania, Philadelphia.
Hud
E
E
Wu
V Y
VY
D000419:Albuminuria / Q000652:urine; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001786:Blood Glucose / Q000032:analysis; D003928:Diabetic Nephropathies / Q000473:pathology / Q000517:prevention & control*; D004797:Enzyme-Linked Immunosorbent Assay; D005920:Glomerular Mesangium / Q000473:pathology; D017127:Glycation End Products, Advanced; D006031:Glycosylation; D051379:Mice; D008817:Mice, Mutant Strains; D012709:Serum Albumin / Q000276:immunology*; D000093423:Glycated Serum Albumin
D000911:Antibodies, Monoclonal; D001786:Blood Glucose; D017127:Glycation End Products, Advanced; D012709:Serum Albumin; D000093423:Glycated Serum Albumin