Abstract
Background:
Statins elicit antioxidant effects independently of their lipid-lowering properties. Heme oxygenase-1 (HO-1) induction may be a part of these pleiotropic effects, which are insufficiently described in the kidney. We hypothesize that simvastatin (SIM) transcriptionally activates HO-1 that protects renal proximal tubule cells from lipotoxic injury.
Methods:
Impact of SIM on 100 μmol/l oleic acid (OA)-mediated reactive oxygen species (ROS) production and consequent oxidative stress (4-hydroxynonenal (HNE) content) as well as cell injury/apoptosis (lactate dehydrogenase (LDH) release, caspase-3 activation) were determined in cultured renal proximal tubule (NRK52E) cells. Effect of SIM on the HO-1 promoter and its enhancer elements (antioxidant response element (ARE), CCAAT, AP1, and cAMP response element (CRE)) was also determined in reporter luciferase assays. Dominant-negative (dnMEK, M1CREB) and pharmacologic (H89) approaches were used to inhibit activation of extracellular signal regulated kinase (ERK), CREB, and protein kinase A (PKA), respectively.
Results:
SIM dose-dependently activated the HO-1 promoter that was essential for protection against OA-dependent ROS production/oxidative stress and LDH release/caspase-3 activation. We found that the HO-1 promoter was induced through ERK and PKA-dependent activation of the CRE by SIM.
Conclusion:
SIM may protect the kidney from adverse effects of circulating fatty acids by upregulating the antioxidant HO-1, aside from its well-described lipid-lowering effects.
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Acknowledgements
The authors thank Alam for the HO-1 promoter luciferase, Greenberg for the M1CREB, and Weber for the dnMEK construct.
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Barnett, M., Hall, S., Dixit, M. et al. Simvastatin attenuates oleic acid-induced oxidative stress through CREB-dependent induction of heme oxygenase-1 in renal proximal tubule cells. Pediatr Res 79, 243–250 (2016). https://doi.org/10.1038/pr.2015.210
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DOI: https://doi.org/10.1038/pr.2015.210
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