Inhibiting albumin glycation attenuates dysregulation of VEGFR-1 and collagen IV subchain production and the development of renal insufficiency.
Glomerular cells in culture respond to albumin containing Amadori glucose adducts (the principal serum glycated protein), with activation of protein kinase C-beta(1), increased expression of transforming growth factor (TGF)-beta1, the TGF-beta type II signaling receptor, and the extracellular matrix proteins alpha(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-beta1 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 alpha(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.
Cohen
Margo P
MP
University City Science Center, Philadelphia, Pennsylvania, USA. drmpcohen@aol.com
Lautenslager
Gregory T
GT
Hud
Elizabeth
E
Shea
Elizabeth
E
Wang
Amy
A
Chen
Sheldon
S
Shearman
Clyde W
CW
D000418:Albumins / Q000737:chemistry; D000818:Animals; D024141:Collagen Type IV / Q000096:biosynthesis*; D003404:Creatinine / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000494:pharmacology; D006031:Glycosylation / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008820:Mice, Obese; D051437:Renal Insufficiency / Q000517:prevention & control*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*
C518289:2-(3-chlorophenylamino)phenylacetic acid; D000418:Albumins; D024141:Collagen Type IV; D008565:Membrane Proteins; C113267:nephrin; D004008:Diclofenac; D003404:Creatinine; D040281:Vascular Endothelial Growth Factor Receptor-1