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      Molecular Mechanism of Oxalate-Induced Free Radical Production and Glutathione Redox Imbalance in Renal Epithelial Cells: Effect of Antioxidants

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          Background: Peroxidation of renal cells is a critical event in the nucleation and formation of calcium oxalate crystals under hyperoxaluric conditions. We previously demonstrated that oxalate-induced peroxidative injury is one of the major mechanisms in promoting crystal attachment to renal epithelial cells. Methods: In this study we have demonstrated that the mechanism of oxalate-induced peroxidative injury is through the induction of TGF-β<sub>1</sub> and glutathione (GSH) redox imbalance in LLC-PK<sub>1</sub> cells. Results: LLC-PK<sub>1</sub>, renal epithelial cells exposed to oxalate had significantly higher reactive oxygen species (ROS) production; higher TGF-β<sub>1</sub> levels, as measured by ELISA (1.89 ± 0.035 fold increase) or Western blot (1.65 ± 0.01 fold increase); increased malondialdehyde formation; increased LDH release, and loss of cell viability. In addition, oxalate exposure significantly decreased GSH content, glutathione reductase, glucose-6-phosphate dehydrogenase activities, and increased oxidized GSH content. Treatment with vitamin E, neutralizing anti-TGF-β antibody, or diphenylene iodium, an inhibitor of NAD(P)H oxidase, significantly inhibited oxalate-induced ROS production and prevented peroxidative injury and cytolysis. Vitamin E, catalase, or desferoxamine treatment also significantly restored the oxalate-induced cellular GSH redox status toward the control level, and vitamin E treatment significantly attenuated the oxalate-mediated increase in TGF-β<sub>1</sub> protein in cultured LLC-PK<sub>1</sub> cells. Conclusions: This is the first study to demonstrate that the mechanism of oxalate-induced free radical production in renal tubular epithelial cells is through the activation of NAD(P)H oxidase via cytokine TGF-β<sub>1</sub> induction. These results also provide direct evidence that antioxidant therapy might prevent calcium oxalate nucleation and kidney stone formation by preventing oxalate-mediated peroxidative injury and GSH redox imbalance.

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          Most cited references 20

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          Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: Applications to mammalian blood and other tissues

           Frank Tietze (1969)
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            Suppression of experimental glomerulonephritis by antiserum against transforming growth factor beta 1.

            Glomerulonephritis is an inflammation of the kidney characterized by the accumulation of extracellular matrix within the damaged glomeruli, impaired filtration and proteinuria. In its progressive form, the disease destroys kidney function leading to uraemia and death, unless dialysis therapy or kidney transplantation is available. The pathogenesis of glomerulonephritis is incompletely understood, but the eliciting factor is thought often to be an immunological injury to mesangial and/or other resident cells in the glomeruli. We have used an animal model of acute mesangial proliferative glomerulonephritis to show that this disease is associated with increased production and activity of transforming growth factor beta 1 (TGF-beta 1), an inducer of extracellular matrix production. Here we report that administration of anti-TGF-beta 1 at the time of induction of the glomerular disease suppresses the increased production of extracellular matrix and dramatically attenuates histological manifestations of the disease. These results provide direct evidence for a causal role of TGF-beta 1 in the pathogenesis of the experimental disease and suggest a new approach to the therapy of glomerulonephritis.
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              Activation of an H2O2-generating NADH Oxidase in Human Lung Fibroblasts by Transforming Growth Factor β1


                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                October 2004
                01 December 2004
                : 24
                : 5
                : 557-568
                Department of Urology, Vattikuti Urology Institute and Henry Ford Health Sciences Center, Detroit, Mich., USA
                82043 Am J Nephrol 2004;24:557–568
                © 2004 S. Karger AG, Basel

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                Page count
                Figures: 8, Tables: 1, References: 41, Pages: 12
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                Original Report: Laboratory Investigation


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