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The Antioxidant N-Acetylcysteine Induces Mesangial Cells to Create Three-Dimensional Cytoarchitecture That Underlies Cellular Differentiation

Glomerular Bioengineering Unit, Department of Medicine, University College London Medical School, The Rayne Institute, London, United Kingdom.

Correspondence to Dr. Masanori Kitamura, Glomerular Bioengineering Unit, Department of Medicine, University College London Medical School, The Rayne Institute, 5 University Street, London WC1E 6JJ, United Kingdom. Phone: +44-171-209-6191; Fax: +44-171-209-6211; E-mail: m.kitamura{at}medicine.ucl.ac.uk

Abstract. Prolonged culture of mesangial cells produces multifocal nodular structures, i.e., "hillocks," consisting of cells and extracellular matrix. Hillock formation is associated with induction of a differentiated phenotype of mesangial cells, with suppressed mitogenesis and downregulation of -smooth muscle actin (-SMA). Currently, little is understood regarding physiologically relevant factors that facilitate this cytodifferentiation. This study explores whether and how the cellular redox state modulates hillock formation. Exposure of confluent rat mesangial cells to the antioxidant N-acetylcysteine (NAC), an inducer of glutathione, dramatically facilitated hillock formation. This effect was mimicked by external addition of the reduced form of glutathione ethyl ester. In contrast, the oxidizing agents diamide and menadione inhibited the development of hillocks triggered by either NAC, glutathione, or prolonged culture. The induction of hillocks by NAC was correlated with downregulation of -SMA as well as attenuated activity of the CArG box element (the cis-element relevant to the expression of the -SMA gene and growth-associated genes). These results indicate that, by a redox-sensitive mechanism, NAC induces mesangial cells to create three-dimensional cytoarchitecture that underlies cellular differentiation.

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