AMELIORATION OF DIABETIC NEPHROPATHY BY TREATMENT WITH MONOCLONAL-ANTIBODIES AGAINST GLYCATED ALBUMIN

The pathogenesis of diabetic nephropathy is incompletely understood, b ut increased nonenzymatic glycation of proteins is considered an impor tant contributory factor. Glycated albumin, which is increased in diab etic sera and is preferentially transported into the renal glomerulus, induces an increase in Type TV collagen production and a decrease in proliferative capacity by mesangial cells in culture. These effects re semble 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 possib ility that the in vitro effects of glycated albumin on mesangial cell biology pertain to the in vivo situation, we examined the effect of tr eatment with the A717 monoclonal antibodies on glomerular functional a nd 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 ob served in the untreated db/db mice that served as controls. Monoclonal antibody treatment also was shown to lower plasma concentrations of g lycated albumin in diabetic mice. Thus, reducing glycated albumin conc entrations and/or blocking its biologically active epitopes has a salu tary influence on the pathogenesis of diabetic nephropathy. The findin gs indicate that glycated albumin participates in the development of t he glomerular lesion in the db/db mouse, and suggest a new approach to the therapy of this complication of diabetes.