Prevention of decline in renal function in the diabetic db/db mouse.
We recently reported that when diabetic db/db mice, which develop glomerular pathology resembling that in human diabetes mellitus, are treated with monoclonal antibodies (A717) that neutralize the effects of excess 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 renal 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 immunoglobulin (MIg). Early in the course of diabetes, BUN and serum creatinine concentrations did not significantly differ from those in the db/m littermates, but were significantly increased after 10 weeks of sustained hyperglycaemia. Treatment of db/db mice with A717 prevented the rise in creatinine and attenuated the elevation in BUN. A717 also prevented the 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 in db/db vs db/db-A717 vs db/m, respectively). MIg did not alter the change in renal function with time in db/db mice. Taken together with our previous results, the present findings indicate that the diabetic db/db mouse develops changes in renal function and structure that parallel the course of human diabetic nephropathy in nature and chronology and demonstrate, for the first time, that therapy directed against increased glycated albumin can prevent the decline in renal function in this rodent model of genetic diabetes.
Cohen
M P
MP
University City Science Center, Philadelphia, Pennsylvania, USA.
Clements
R S
RS
Cohen
J A
JA
Shearman
C W
CW
D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D003094:Collagen / Q000096:biosynthesis; D003920:Diabetes Mellitus / Q000097:blood / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000503:physiopathology / Q000517:prevention & control*; D005353:Fibronectins / Q000096:biosynthesis; D015870:Gene Expression; D005920:Glomerular Mesangium / Q000473:pathology / Q000503:physiopathology*; D017127:Glycation End Products, Advanced; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000627:therapeutic use; D007668:Kidney / Q000503:physiopathology*; D007677:Kidney Function Tests; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009765:Obesity; D011507:Proteinuria; D012333:RNA, Messenger / Q000096:biosynthesis; D012709:Serum Albumin / Q000276:immunology*; D013997:Time Factors; D000093423:Glycated Serum Albumin
D000911:Antibodies, Monoclonal; D001786:Blood Glucose; D005353:Fibronectins; D017127:Glycation End Products, Advanced; D007140:Immunoglobulin Fab Fragments; D012333:RNA, Messenger; D012709:Serum Albumin; D003094:Collagen; D000093423:Glycated Serum Albumin