alexa Oxidative stress mediates protein kinase C activation and advanced glycation end product formation in a mesangial cell model of diabetes and high protein diet.
Diabetes & Endocrinology

Diabetes & Endocrinology

Journal of Diabetes & Metabolism

Author(s): Tuttle KR, Anderberg RJ, Cooney SK, Meek RL

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Abstract BACKGROUND/AIMS: High levels of glucose and/or amino acids increase advanced glycation end products (AGE) and activate protein kinase C (PKC), a key signal for injury in mesangial cells. The aim was to determine whether oxidative stress mediates bidirectional interactions between AGE and PKC ('cross-activation') in this model. METHODS: Rat mesangial cells were examined after 48 h of exposure to: high glucose (30.5 mM), increased amino acids designed to resemble a protein meal, the combination of both conditions, and control. Cells were treated with antioxidants (vitamin E, alpha-lipoic acid, N-acetylcysteine, apocynin, doses based on suppression of reactive oxygen species), PKC inhibitors (calphostin C orPLY379196, 100 nM), or AGE inhibitors (aminoguanidine or pyridoxamine 0.5 mM). RESULTS: Carboxymethyllysine, an AGE marker, increased twofold in mesangial cells exposed to the experimental conditions. Antioxidants and PKC inhibition prevented carboxymethyllysine increases. Likewise, antioxidants and AGE inhibition prevented PKC activation. Inhibition of carboxymethyllysine increases and PKC activation by apocynin indicates a primary role for NADPH oxidase in producing oxidative stress. Induction of transforming growth factor-beta(1) and fibronectin was inhibited by antioxidants and inhibitors of PKC and AGE. CONCLUSIONS: Oxidative stress mediated cross-activation between PKC and AGE in this mesangial cell model of diabetes and high protein diet.PKC may amplify cellular injury by promoting AGE accumulation. 2008 S. Karger AG, Basel. This article was published in Am J Nephrol and referenced in Journal of Diabetes & Metabolism

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