Evidence linking glycated albumin to altered glomerular nephrin and VEGF expression, proteinuria, and diabetic nephropathy.
BACKGROUND
Albumin modified by Amadori-glucose adducts has been linked to the development of diabetic nephropathy through its ability, independent of hyperglycemia, to activate protein kinase C-beta (PKC-beta), up-regulate the transforming growth factor-beta (TGF-beta) system, and stimulate expression of extracellular matrix proteins in glomerular cells, and by the demonstration that reducing the burden of glycated albumin ameliorates renal structural and functional abnormalities in the db/db mouse.


METHODS
To probe whether the salutary effects consequent to lowering glycated albumin, which include reduction of albuminuria, relate to an influence of the Amadori-modified protein on nephrin, the podocyte protein critical to regulation of protein excretion, and on the angiogenic vascular endothelial growth factor (VEGF), which induces microvascular permeability, diabetic db/db mice were treated with a small molecule that inhibits the nonenzymatic glycation of albumin.


RESULTS
Compared to nondiabetic db/m mice, diabetic controls exhibited increased urinary excretion of albumin and type IV collagen, elevated renal TGF-beta1 protein levels, reduced glomerular nephrin immunofluorescence and nephrin protein by immunoblotting, and increased glomerular VEGF immunostaining and renal VEGF protein content. Diabetic animals receiving test compound showed significant lowering of proteinuria, normalization of renal TGF-beta1 protein, and significant restoration of altered glomerular nephrin and VEGF expression.


CONCLUSIONS
The findings causally implicate the increased glycated albumin associated with the diabetic state in the abnormal renal nephrin and VEGF expression found in diabetes, thereby promoting proteinuria and glomerulosclerosis.
Cohen
Margo P
MP
University City Science Center, Institute of Metalboic Research, Philadelphia, Pennsylania 19104, USA. drmpcohen@aol.com
Chen
Sheldon
S
Ziyadeh
Fuad N
FN
Shea
Elizabeth
E
Hud
Elizabeth A
EA
Lautenslager
Gregory T
GT
Shearman
Clyde W
CW
D000419:Albuminuria / Q000378:metabolism; D000818:Animals; D024141:Collagen Type IV / Q000652:urine; D003928:Diabetic Nephropathies / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D017127:Glycation End Products, Advanced; D007678:Kidney Glomerulus / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D011507:Proteinuria / Q000378:metabolism*; D012709:Serum Albumin / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D000093423:Glycated Serum Albumin
D024141:Collagen Type IV; D017127:Glycation End Products, Advanced; D008565:Membrane Proteins; D012709:Serum Albumin; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; C113267:nephrin; D000093423:Glycated Serum Albumin