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1 Division og Nephrology, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
2 Laboratory of Kidney and Electrolyte Metabolism, NHLBI, NIH, Bethesda, MD, USA
3 Division of Nephrology and Hypertension, University of Alabama at Birmingham, Birmingham, AL, USA
* To whom correspondence should be addressed. E-mail: xiazhou{at}usuhs.mil.
The signaling pathways leading to high NaCl-induced activation of the transcription factor TonEBP/OREBP remain incompletely understood. High NaCl has been reported to produce oxidative stress. Reactive oxygen species (ROS), which are a component of oxidative stress, contribute to regulation of transcription factors. The present study was undertaken to test whether high NaCl-induced increase of ROS contributes to tonicity-dependent activation of TonEBP/OREBP. HEK293 cells were used as a model. We find that raising NaCl increases ROS, including superoxide. N-acetylcysteine (NAC), an antioxidant, and MnTBAP, an inhibitor of superoxide, reduce high NaCl-induced superoxide activity and suppress both high NaCl-induced increase in TonEBP/OREBP transcriptional activity and high NaCl-induced increase in expression of BGT1 mRNA, a transcriptional target of TonEBP/OREBP. Catalase, which decomposes hydrogen peroxide, does not have these effects, whether applied exogenously or overexpressed within the cells. Further, NAC and MnTBAP, but not catalase, blunt high NaCl-induced increase in TonEBP/OREBP transactivation. L-NMMA, a general inhibitor of nitric oxide synthase, has no significant effect on either high NaCl-induced increase in superoxide or TonEBP/OREBP transcriptional activity, suggesting that the effects of ROS do not involve nitric oxide. Ouabain, an inhibitor of Na, K-ATPase, attenuates high NaCl-induced superoxide activity and inhibits TonEBP/OREBP transcriptional activity. We conclude that high NaCl-induced increase of ROS, including superoxide, contributes to activation of TonEBP/OREBP by increasing its transactivation.
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