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α-Tocopherol protects renal cells from nicotine- or oleic acid-provoked oxidative stress via inducing heme oxygenase-1

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Abstract

Smoking and obesity increases renal oxidative stress via nicotine (NIC) or free fatty acid such as oleic acid (OA) but decreases levels of the vitamin E-derivative α-tocopherol (TOC), which has shown to stimulate the antioxidant system such as heme oxygenase-1 (HO-1). Hence, we hypothesized that supplementation of TOC may protect renal proximal tubules from NIC- or OA-mediated oxidative stress by upregulating the HO-1 gene. NIC- or OA-dependent production of reactive oxygen species (ROS) was determined in the presence or absence of various pharmacologic or genetic inhibitors that modulate HO-1 activation and enhancer elements in the HO-1 promoter such as the antioxidant response element (ARE) and the cAMP-response element (CRE) in renal proximal tubule cells (NRK52E). Activity of the HO-1 promoter, the ARE and the CRE was determined in luciferase assays. We found that pre- or posttreatment with TOC attenuated NIC- or OA-dependent ROS production that required HO-1 activation. TOC activated the HO-1 promoter via the CRE but not the ARE enhancer through the extracellular signal-regulated kinase (ERK) and protein kinase A (PKA). Consequently, inhibitors of ERK, PKA, or CRE activation mitigated beneficial effects of TOC on NIC- or OA-mediated ROS production. Hence, vitamin E supplementation—via induction of the cytoprotective HO-1—may help to reduce renal oxidative stress imposed by smoking or obesity.

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Acknowledgments

This work was supported by a grant provided by an American Heart Association Grant-in-Aid 10GRNT3790019 (to I.A.) as well as an IRSP Grant from the UMMC (to I.A.). The authors wish to thank to Dr. Alam for the HO-1-promoter luciferase plasmid, to Dr. Greenberg for the M1CREB plasmid, and to Dr. Weber for the dnMEK plasmid.

Conflict of interest

The authors do not declare any conflict of interest. The results presented in this paper have not been published previously in whole or part, except in abstract format.

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  1. Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS, USA

    Dustin K. Reed, Samuel Hall & Istvan Arany

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  1. Dustin K. Reed
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  3. Istvan Arany
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Correspondence to Istvan Arany.

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Fig6

Supplementary Figure. Activation of the HO-1 promoter by TOC is temporal and depends on its concentration. NRK52E cells were transfected with a HO-1-promoter plasmid together with a renilla luciferase and treated with increasing concentration of TOC, as indicated. Luciferase activities were determined after 24 hours treatment. Results were calculated as firefly/renilla ratios and expressed as percentage of untreated values. N = 3, *p < 0.05 compared to untreated control (GIF 17 kb)

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Reed, D.K., Hall, S. & Arany, I. α-Tocopherol protects renal cells from nicotine- or oleic acid-provoked oxidative stress via inducing heme oxygenase-1. J Physiol Biochem 71, 1–7 (2015). https://doi.org/10.1007/s13105-014-0372-x

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