title: Modification of collagen IV by glucose or methylglyoxal alters distinct mesangial cell functions.
abstract: Diabetic nephropathy (DN) affects both glomerular cells and the extracellular matrix (ECM), yet the pathogenic mechanisms involving cell-matrix interactions are poorly understood. Glycation alters integrin-dependent cell-ECM interactions, and perturbation of these interactions results in severe renal pathology in diabetic animals. Here, we investigated how chemical modifications of the ECM by hyperglycemia and carbonyl stress, two major features of the diabetic milieu, affect mesangial cell functions. Incubation of collagen IV with pathophysiological levels of either the carbonyl compound methylglyoxal (MGO) or glucose resulted in modification of arginine or lysine residues, respectively. Mouse mesangial cells plated on MGO-modified collagen IV showed decreased adhesion and migration. Cells plated on glucose-modified collagen IV showed reduced proliferation and migration and increased collagen IV production. Inhibiting glucose-mediated oxidative modification of collagen IV lysine residues rescued the alterations in cell growth, migration, and collagen synthesis. We propose that diabetic ECM affects mesangial cell functions via two distinct mechanisms: modification of arginine residues by MGO inhibits cell adhesion, whereas oxidative modification of lysine residues by glucose inhibits cell proliferation and increases collagen IV production. These mechanisms may contribute to mesangial cell hypertrophy and matrix expansion in DN.
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Ambra
authors.initials: A
authors.lastname: Pozzi
authors.forename: Roy
authors.initials: R
authors.lastname: Zent
authors.forename: Sergei
authors.initials: S
authors.lastname: Chetyrkin
authors.forename: Corina
authors.initials: C
authors.lastname: Borza
authors.forename: Nada
authors.initials: N
authors.lastname: Bulus
authors.forename: Peale
authors.initials: P
authors.lastname: Chuang
authors.forename: Dong
authors.initials: D
authors.lastname: Chen
authors.forename: Billy
authors.initials: B
authors.lastname: Hudson
authors.forename: Paul
authors.initials: P
authors.lastname: Voziyan
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000209:etiology*; D005947:Glucose / Q000633:toxicity*; D050527:Mesangial Cells / Q000502:physiology*; D051379:Mice; D011765:Pyruvaldehyde / Q000633:toxicity*
chemical_list: D024141:Collagen Type IV; D011765:Pyruvaldehyde; D005947:Glucose