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      Role of oxidative stress in advanced glycation end product-induced mesangial cell activation.

      Kidney International

      Cells, Cultured, Dose-Response Relationship, Drug, Enzyme Activation, physiology, Glomerular Mesangium, cytology, drug effects, Glutathione, antagonists & inhibitors, Glycosylation End Products, Advanced, pharmacology, Hydrogen Peroxide, Male, Maleates, Transforming Growth Factor beta1, NF-kappa B, Oxidants, Oxidative Stress, Protein Kinase C, metabolism, Rats, Rats, Sprague-Dawley, Reactive Oxygen Species, Serum Albumin, Bovine, Transforming Growth Factor beta, Animals

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          Levels of advanced glycation end products (AGE) are elevated in individuals with advancing age, renal failure, and diabetes, and accumulation of these molecules may contribute to disease progression. The mechanism by which AGE proteins alter glomerular mesangial cell function, however, is not completely understood. The present study assessed the involvement of oxidative stress in AGE-dependent mesangial cell signaling events. Primary cultures of rat renal mesangial cells were exposed to in vitro AGE-BSA and H2O2. Nuclear factor-kappaB (NF-kappaB) and protein kinase C (PKC) isoform activation were studied using confocal microscopy and Western blotting. Quantitative polymerase chain reaction (PCR) was used to measure transforming growth factor-beta1 (TGF-beta1) levels. The involvement of oxidative stress was assessed by supplementing or compromising cellular antioxidant capacity. NF-kappaB was dose-dependently activated by AGE. PKC activation was not involved in this response, but analysis of PKC-beta1 activation showed a stimulatory effect of AGE proteins on this isoform. Transcription of TGF-beta1 was stimulated by AGE and was prevented by PKC inhibition. Challenge with H2O2 had similar downstream effects on mesangial cell signaling. Antioxidants, vitamin E and nitecapone, prevented AGE-dependent NF-kappaB activation and normalized PKC activity and associated TGF-beta1 transcription. Depletion of the intracellular antioxidant, glutathione, effectively lowered the AGE concentration needed for mesangial cell activation of NF-kappaB and PKC-beta1. Treatment with a suboptimal AGE dose, under glutathione-depleted conditions, revealed a synergistic effect on both parameters. The results support a central role for oxidative stress in AGE-dependent mesangial cell signaling and emphasize the importance of ROS in determining cell responsiveness.

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