Glomerular cells in culture respond to albumin containing Amadori glucose adducts, the principal serum glycated protein, with activation of PKC-1, increased expression of TGF-1, the TGF- type II signaling receptor, and the extracellular matrix proteins 1(IV) collagen and fibronectin, and 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 VEGF immunostaining. In the present study, db/db mice were treated with a small molecule, designated 23CPPA, which inhibits the nonenzymatic condensation of glucose with the albumin protein to evaluate whether increased glycated albumin influences the production of VEGF receptors and type IV collagen subchains and ameliorates the development of renal insufficiency. Compared to age-matched nondiabetic (db/m) mice, control diabetic animals had significantly higher renal levels of VEGF and VEGFR-1 proteins and serum creatinine concentrations, and significantly lower renal levels of 3(IV) collagen and nephrin proteins and endogenous creatinine clearance values. These changes were significantly attenuated in db/db littermate mice treated from age 9 to 18 weeks 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.