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.

The pathogenesis of diabetic nephropathy is incompletely understood, but increased nonenzymatic glycation of proteins is considered an important contributory factor. Glycated albumin, which is increased in diabetic sera and is preferentially transported into the renal glomerulus, induces an increase in Type IV collagen production and a decrease in proliferative capacity by mesangial cells in culture. These effects resemble the abnormalities that characterize the glomerular mesangium in diabetes and are prevented by monoclonal antibodies that specifically react with Amadori adducts in glycated albumin. To explore the possibility that the in vitro effects of glycated albumin on mesangial cell biology pertain to the in vivo situation, we examined the effect of treatment with the A717 monoclonal antibodies on glomerular functional and structural changes in a rodent model of genetic diabetes, the db/db mouse. Weekly parenteral antibody administration reduced the elevated albumin excretion and attenuated the mesangial expansion that were observed in the untreated db/db mice that served as controls. Monoclonal antibody treatment also was shown to lower plasma concentrations of glycated albumin in diabetic mice. Thus, reducing glycated albumin concentrations and/or blocking its biologically active epitopes has a salutary influence on the pathogenesis of diabetic nephropathy. The findings indicate that glycated albumin participates in the development of the glomerular lesion in the db/db mouse, and suggest a new approach to the therapy of this complication of diabetes.

These findings, to our knowledge, provide the first evidence that glomerular overexpression of TGF-beta1 in diabetes derives at least in part from elevated glycated albumin concentrations, and can be partially suppressed by inhibiting the formation of this glycated protein. The results further suggest that glycated albumin has an important nephropathogenic role in diabetes that is operative, and can be therapeutically addressed, independent of glycemic status.

CW. Inhibiting albumin glycation attenuates dysregulation of VEGFR-1 and collagen IV subchain production and the development of renal insufficiency. Am J Physiol Renal Physiol 292: F789 -F795, 2007. First published October 3, 2006; doi:10.1152/ajprenal.00201.2006.-Glomerular cells in culture respond to albumin containing Amadori glucose adducts (the principal serum glycated protein), with activation of protein kinase C-␤1, increased expression of transforming growth factor (TGF)-␤1, the TGF-␤ type II signaling receptor, and the extracellular matrix proteins ␣1(IV) collagen and fibronectin and with decreased production of the podocyte protein nephrin. Decreasing the burden of glycated albumin in diabetic db/db mice significantly reduces glomerular overexpression of TGF-␤1 mRNA, restores glomerular nephrin immunofluorescence, and lessens proteinuria, mesangial expansion, renal extracellular matrix protein production, and increased glomerular vascular endothelial growth factor (VEGF) immunostaining. In the present study, db/db mice were treated with a small molecule, designated 23CPPA, that inhibits the nonenzymatic condensation of glucose with the albumin protein to evaluate whether increased glycated albumin influences the production of VEGF receptors (VEGFRs) and type IV collagen subchains and ameliorates the development of renal insufficiency. Renal levels of VEGF and VEGFR-1 proteins and serum creatinine concentrations were significantly higher and renal levels of ␣3(IV) collagen and nephrin proteins and endogenous creatinine clearance values were significantly lower in control diabetic than in age-matched nondiabetic (db/m) mice. These changes were significantly attenuated in db/db littermate mice treated from 9 to 18 wk of age with 23CPPA. The findings indicate that inhibiting excess nonenzymatic glycation of serum albumin improves renal molecular biology abnormalities and protects against the development of renal insufficiency in the db/db mouse. diabetes; glycated albumin GLOMERULAR CELLS IN CULTURE respond, in a euglycemic milieu, to albumin modified by Amadori glucose adducts with activation of protein kinase C-␤ 1 and extracellular signal-regulated kinase, upregulation of the transforming growth factor (TGF)-␤ system, increased production of extracellular matrix proteins, and reduced expression of the podocyte protein nephrin (4,6,12,13,15,19). The relevance of these observations to the pathogenesis of diabetic nephropathy in vivo is supported by results of animal studies, which have shown that treatment of diabetic db/db mice with a small molecule that inhibits the nonenzymatic glycation of serum albumin decreases the glomerular mRNA expression of TGF-␤1, prevents depletion of glomerular nephrin (quantified by immunofluorescence), ameliorates mesangial expansion and mRNA overexpression of the extracellular matrix proteins ␣ 1 (IV) collagen and fibronectin, and lessens the urinary excretion of albumin and type IV collagen (measured as mg/24 h and ng/24 h, respectively) (9, 14). This treatment has also b...

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