Inhibiting albumin glycation ameliorates diabetic nephropathy in the db/db mouse.
Albumin modified by Amadori glucose adducts stimulates the expression of extracellular matrix proteins by glomerular mesangial and endothelial cells, and has been mechanistically linked to the pathogenesis of diabetic nephropathy. To test the hypothesis that inhibiting the formation of glycated albumin might beneficially influence the development of kidney disease in diabetes, we treated diabetic db/db mice for 12 weeks with a low-molecular-weight compound (EXO-226) that impedes the condensation of free glucose with lysine epsilon-amino groups in albumin. Administration of EXO-226 (3 mg/kg) twice daily by gavage normalized the plasma concentration of glycated albumin within days after initiation of treatment and maintained glycated albumin within the normal range throughout the study, despite persistent and severe hyperglycemia. Urine albumin excretion, which was markedly increased at the start of the study (age 12 weeks), was significantly reduced in treated diabetic animals compared with their untreated diabetic littermates. The fall in creatinine clearance that was observed in untreated diabetic animals was prevented in diabetic littermates that received treatment. Compared with the nondiabetic controls, the amount of glomerular mesangial matrix was threefold greater in untreated diabetic mice; in contrast, the mesangial matrix fraction was only 1. 5 times that of nondiabetic controls in the treated diabetic animals, representing a reduction in mesangial matrix accumulation of more than 50%. EXO-226 also reduced the overexpression of mRNA encoding for alpha1 (IV) collagen in renal cortex of db/db mice. We conclude that normalization of plasma glycated albumin concentrations with the glycation inhibitor EXO-226 ameliorates the glomerular structural and functional abnormalities associated with diabetic nephropathy in the db/db mouse.
Cohen
M P
MP
University City Science Center, Philadelphia, PA, USA. drmpcohen@AOL.com
Masson
N
N
Hud
E
E
Ziyadeh
F
F
Han
D C
DC
Clements
R S
RS
D000419:Albuminuria / Q000652:urine; D000818:Animals; D003094:Collagen / Q000235:genetics; D003404:Creatinine / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology* / Q000652:urine; D005109:Extracellular Matrix / Q000378:metabolism; D005920:Glomerular Mesangium / Q000378:metabolism / Q000473:pathology; D017127:Glycation End Products, Advanced; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains / Q000235:genetics; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D012016:Reference Values; D012709:Serum Albumin / Q000032:analysis / Q000037:antagonists & inhibitors*; D000093423:Glycated Serum Albumin
D017127:Glycation End Products, Advanced; D012333:RNA, Messenger; D012709:Serum Albumin; D003094:Collagen; D003404:Creatinine; D000093423:Glycated Serum Albumin