Prevention of diabetic nephropathy in db/db mice with glycated albumin antagonists. A novel treatment strategy.
Accelerated protein glycation in diabetes has been mechanistically linked to the pathogenesis of diabetic nephropathy. Because glycated albumin induces abnormalities in cultured mesangial cells that resemble those characterizing the glomerular mesangium in diabetes, and monoclonal antibodies (A717) specific for Amadori-modified glycated albumin prevent these abnormalities, we postulated that in vivo administration of A717 could retard the progression of diabetic nephropathy. To test this hypothesis, diabetic db/db mice and their nondiabetic db/m littermates were treated with eight consecutive weekly injections of 150 micrograms of A717 (Fab fragments) to reduce the elevated plasma glycated albumin concentration, or with irrelevant murine IgG (MIg). Relative to nondiabetics, diabetic mice (MIg treated) manifested proteinuria (3.35 +/- 0.15 vs 0.87 +/- 0.1 mg albumin/mg creatinine), 3.8-fold increase in mesangial matrix fraction, and renal cortical overexpression of mRNAs encoding alpha 1(IV) collagen (2.6-fold increase) and fibronectin (3.8-fold increase). Treatment of db/db mice with A717 significantly reduced the proteinuria (1.52 +/- 0.3 mg/mg creatinine), inhibited mesangial matrix expansion, and attenuated overexpression of matrix mRNAs. The nephropathic protective effects of A717 were independent of any change in blood glucose concentrations. Antibodies unreactive with glycated albumin did not duplicate the beneficial effects of A717. Thus, abrogating the biologic effects of increased glycated albumin with A717 has a salutary influence on the pathogenesis of diabetic nephropathy and has novel therapeutic potential in its management.
Cohen
M P
MP
Department of Biochemistry, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Sharma
K
K
Jin
Y
Y
Hud
E
E
Wu
V Y
VY
Tomaszewski
J
J
Ziyadeh
F N
FN
D000419:Albuminuria; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism; D015152:Blotting, Northern; D001835:Body Weight; D003094:Collagen / Q000096:biosynthesis; D003928:Diabetic Nephropathies / Q000473:pathology / Q000517:prevention & control*; D005353:Fibronectins / Q000096:biosynthesis; D015870:Gene Expression; D005920:Glomerular Mesangium / Q000378:metabolism / Q000473:pathology; D017127:Glycation End Products, Advanced; D006031:Glycosylation; D007140:Immunoglobulin Fab Fragments / Q000627:therapeutic use*; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D007672:Kidney Cortex / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009929:Organ Size; D011507:Proteinuria; D012709:Serum Albumin / Q000037:antagonists & inhibitors* / Q000276:immunology; D000093423:Glycated Serum Albumin
D000911:Antibodies, Monoclonal; D001786:Blood Glucose; D005353:Fibronectins; D017127:Glycation End Products, Advanced; D007140:Immunoglobulin Fab Fragments; D012709:Serum Albumin; D003094:Collagen; D000093423:Glycated Serum Albumin