Received August 27, 2008
Accepted on May 13, 2009

BRIEF COMMUNICATION

Modification of Collagen IV by Glucose or Methylglyoxal Alters Distinct Mesangial Cell Functions

Ambra Pozzi ^*, Roy Zent ^*, Sergei Chetyrkin ^*, Corina Borza ^*, Nada Bulus ^*, Peale Chuang ^*, Dong Chen ^*, Billy Hudson ^*||, and Paul Voziyan ^*||1

*Division of Nephrology, Department of Medicine, ||Department of Biochemistry, Department of Cancer Biology, and Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee; and Department of Medicine, Veterans Affairs Hospital, Nashville, Tennessee

¹ To whom correspondence should be addressed. E-mail: paul.voziyan{at}vanderbilt.edu.

	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.