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Aldose Reductase-Regulated Tumor Necrosis Factor- Production Is Essential for High Glucose-Induced Vascular Smooth Muscle Cell Growth

Department of Biochemistry and Molecular Biology (K.V.R., R.T., A.B.M.R., S.K.S.), University of Texas Medical Branch, Galveston, Texas 77555-0647; and Institute of Molecular Cardiology (A.B.), University of Louisville, Louisville, Kentucky 40202

Address all correspondence and requests for reprints to: Satish K. Srivastava, Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555-0647. E-mail: ssrivast{at}utmb.edu.

Diabetes is associated with increased generation of cytokines and tissue inflammation, but it is unclear how increased cytokine synthesis is causally related to the development of diabetic complications. Here, we report that exposure to high (25 mM) glucose, but not iso-osmotic concentrations of mannitol or 3-methyl glucose, increased TNF- secretion by rat and human aortic smooth muscle cells in culture. The increase in TNF- production was prevented by actinomycin D and cycloheximide, indicating transcriptional activation of TNF- gene. High glucose (HG)-induced TNF- release was specifically inhibited by protein kinase C (PKC)- inhibitor (Rottlerin; EMD Biosciences, San Diego, CA), but not PKC-ß2 inhibitor (CGP53353; Tocris Cookson Inc., Ellisville, MO), indicating the possible involvement of PKC- in HG signaling. TNF- secretion was also prevented by pretreating cells with aldose reductase (AR) inhibitors, sorbinil or tolrestat and in cells treated with antisense AR mRNA. Inhibition of AR also prevented the increase in TNF- mRNA. Addition of anti-TNF- antibodies or soluble TNF- receptors 1 and 2 to the medium or RNA interference ablation of TNF- attenuated nuclear factor-B activation and prevented HG-stimulated cell growth. These data indicate that AR is required for HG-induced TNF- synthesis and release. In vivo, the release of TNF- by HG leading to autocrine stimulation of TNF- synthesis may be a critical step in the development of the cardiovascular complications of diabetes. Interruption of the autocrine effects of TNF- may be a useful strategy for treating diabetic vasculopathies.

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