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High extracellular glucose plays a pivotal role in the pathophysiology of diabetic nephropathy. Here we report 200 genes, identified using suppression-subtractive hybridization, that are differentially expressed when human mesangial cells are propagated in high ambient glucose in vitro. The major functional classes of genes identified included modulators and products of extracellular matrix protein metabolism, regulators of cell growth and turnover, and a cohort of actin cytoskeleton regulatory proteins. Actin cytoskeletal disassembly is a prominent feature of diabetic nephropathy. The induction of actin cytoskeleton regulatory gene expression by high glucose was attenuated by the inhibitor of reactive oxygen species generation, carbonyl cyanide m-chlorophenylhydrazone but not by the protein kinase C inhibitor GF 109203X and was not mimicked by the addition of transforming growth factor beta. Enhanced expression of actin cytoskeleton regulatory genes was also observed following disruption of the mesangial cell actin cytoskeleton by cytochalasin D. In aggregate, these results suggest that the induction of genes encoding actin cytoskeleton regulatory proteins (a) is a prominent component of the mesangial cell transcriptomic response in diabetic nephropathy and (b) is dependent on oxidative stress, is independent of protein kinase C and transforming growth factor-beta, and represents an adaptive response to actin cytoskeleton disassembly.

Original publication

DOI

10.1074/jbc.M109172200

Type

Journal article

Journal

J Biol Chem

Publication Date

22/03/2002

Volume

277

Pages

9707 - 9712

Keywords

Actins, Animals, Blotting, Northern, Cell Line, Cells, Cultured, Contractile Proteins, Cytochalasin D, Cytoskeleton, DNA, Complementary, Diabetes Mellitus, Experimental, Enzyme Inhibitors, Gene Expression Regulation, Glomerular Mesangium, Glucose, Humans, Indoles, Kidney, Maleimides, Microfilament Proteins, Molecular Sequence Data, Nucleic Acid Hybridization, Oxidative Stress, Oxygen, Profilins, Protein Kinase C, Rats, Rats, Wistar, Reactive Oxygen Species, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, Transforming Growth Factor beta, Transforming Growth Factor beta1, Up-Regulation