Mechanism of perturbation of integrin-mediated cell-matrix interactions by reactive carbonyl compounds and its implication for pathogenesis of diabetic nephropathy.
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 alpha3 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(v)beta(3) 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(1)beta(1) 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.
Pedchenko
Vadim K
VK
Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2372, USA.
Chetyrkin
Sergei V
SV
Chuang
Peale
P
Ham
Amy-Joan L
AJ
Saleem
Moin A
MA
Mathieson
Peter W
PW
Hudson
Billy G
BG
Voziyan
Paul A
PA
D000447:Aldehydes / Q000494:pharmacology; D001120:Arginine / Q000737:chemistry; D001665:Binding Sites; D002448:Cell Adhesion / Q000187:drug effects; D002468:Cell Physiological Phenomena / Q000187:drug effects*; D024141:Collagen Type IV / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000209:etiology*; D042783:Endothelial Cells / Q000502:physiology; D005109:Extracellular Matrix / Q000187:drug effects / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000737:chemistry; D005947:Glucose / Q000494:pharmacology; D006037:Glyoxal / Q000494:pharmacology; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D016023:Integrins / Q000502:physiology*; D007668:Kidney / Q000648:ultrastructure*; D007678:Kidney Glomerulus / Q000648:ultrastructure; D011733:Pyridoxamine / Q000494:pharmacology; D011765:Pyruvaldehyde / Q000494:pharmacology*; D014471:Umbilical Veins
D000447:Aldehydes; D024141:Collagen Type IV; D016326:Extracellular Matrix Proteins; D039302:Integrin alphaVbeta3; D016023:Integrins; D006037:Glyoxal; D011733:Pyridoxamine; D011765:Pyruvaldehyde; D001120:Arginine; D005947:Glucose