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Diabetes 54:2952-2960, 2005
© 2005 by the American Diabetes Association, Inc.

Mechanism of Perturbation of Integrin-Mediated Cell-Matrix Interactions by Reactive Carbonyl Compounds and Its Implication for Pathogenesis of Diabetic Nephropathy

Vadim K. Pedchenko1, Sergei V. Chetyrkin1, Peale Chuang1, Amy-Joan L. Ham2,3, Moin A. Saleem4, Peter W. Mathieson4, Billy G. Hudson1,2, and Paul A. Voziyan1

1 Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee
2 Department of Biochemistry, Vanderbilt University Medical Center, Nashville, Tennessee
3 Mass Spectrometry Research Center, Vanderbilt University Medical Center, Nashville, Tennessee
4 Children’s and Academic Renal Unit, University of Bristol, Bristol, U.K

Perturbation of interactions between cells and the extracellular matrix (ECM) of renal glomeruli may contribute to characteristic histopathological lesions found in the kidneys of patients with diabetic nephropathy. However, the mechanism by which the diabetic conditions may affect cell-ECM interactions is unknown. Existing hypotheses suggest a role of glucose in direct modification of ECM. Here, we have demonstrated that carbonyl compound methylglyoxal (MGO) completely inhibited endothelial cell adhesion to recombinant {alpha}3 noncollagenous 1 domain of type IV collagen mediated via a short collagenous region containing RGD (Arg-Gly-Asp) sequence as well as binding of purified {alpha}vß3 integrin to this protein. Specific MGO adducts of the arginine residue were detected within RGD sequence using mass spectrometry. Modification by carbonyl compounds glyoxal or glycolaldehyde had similar but smaller effects. MGO strongly inhibited adhesion of renal glomerular cells, podocytes, and mesangial cells to native collagen IV and laminin-1 as well as binding of collagen IV to its major receptor in glomerular cells, {alpha}1ß1 integrin. In contrast, modification of these proteins by glucose had no effect on cell adhesion. Pyridoxamine, a promising drug for treatment of diabetic nephropathy, protected cell adhesion and integrin binding from inhibition by MGO. We suggest that in diabetes, perturbation of integrin-mediated cell-matrix interactions occurs via the modification of critical arginine residues in renal ECM by reactive carbonyl compounds. This mechanism may contribute to the development of diabetic nephropathy.

Address correspondence and reprint requests to Paul A. Voziyan, Division of Nephrology, Vanderbilt University Medical Center, S-3223 MCN, 1161 21st Ave. S., Nashville, Tennessee 37232-2372. E-mail: paul.voziyan{at}vanderbilt.edu

Abbreviations: CML, carboxymethyl lysine; 3-DG, 3-deoxyglucosone; ECM, extracellular matrix; ELISA, enzyme-linked immunosorbent assay; GBM, glomerular basement membrane; GLA, glycolaldehyde; MGO, methylglyoxal; MS/MS, tandem mass spectrometry; NC1, noncollagenous 1


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