PREVENTION OF DECLINE IN RENAL-FUNCTION IN THE DIABETIC DB DB MOUSE/

We recently reported that when diabetic db/db mice, which develop glom erular pathology resembling that in human diabetes mellitus, are treat ed with monoclonal antibodies (A717) that neutralize the effects of ex cess glycated albumin, there is an amelioration of mesangial expansion , renal overexpression of mRNAs encoding for the extracellular matrix proteins collagen IV and fibronectin, and proteinuria. These findings suggested that A717 might also retard the development of compromised r enal function in this animal model. To examine this possibility, serum creatinine and blood urea nitrogen (BUN) were measured in diabetic db /db mice and their non-diabetic db/m littermates before and after an 8 -week course of treatment with A717 or irrelevant murine immunoglobuli n (MIg). Early in the course of diabetes, BUN and serum creatinine con centrations did not significantly differ from those in the db/m litter mates, but were significantly increased after 10 weeks of sustained hy perglycaemia. Treatment of db/db mice with A717 prevented the rise in creatinine and attenuated the elevation in BUN. A717 also prevented th e decrease in creatinine clearance observed in diabetic compared with non-diabetic animals (2.2 +/- 0.8 vs 4.1 +/- 0.3 vs 5.0 +/- 1.1 ml/h i n db/db vs db/db-A717 vs db/m, respectively). MIg did not alter the ch ange in renal function with time in db/db mice. Taken together with ou r previous results, the present findings indicate that the diabetic db /db mouse develops changes in. renal function and structure that paral lel the course of human diabetic nephropathy in nature and chronology and demonstrate, for the first time, that therapy directed against inc reased glycated albumin can prevent the decline in renal function in t his rodent model of genetic diabetes.