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Piceatannol protects against cisplatin nephrotoxicity via activation of Nrf2/HO-1 pathway and hindering NF-κB inflammatory cascade

  • Sara A. Wahdan
  • Samar S. Azab
  • Doaa A. Elsherbiny
  • Ebtehal El-DemerdashEmail author
Original Article

Abstract

This study investigates the molecular mechanisms of the nephroprotective effect of piceatannol (PIC) against cisplatin-induced nephrotoxicity in rats. PIC (10 mg/kg i.p.) was given for 7 days, starting 2 days before cisplatin single injection (7 mg/kg i.p.). Serum creatinine, blood urea nitrogen (BUN), kidney injury molecule 1, and neutrophil gelatinase-associated lipocalin were used as nephrotoxicity markers. Oxidative stress, inflammatory, and apoptotic markers were determined. In addition, the role of PIC in Nrf2 activation and its subsequent induction of antioxidant enzymes, as well as its potential cross talk with nuclear factor kappa-B, were addressed. PIC reversed cisplatin-induced elevation of nephrotoxicity markers and restored the normal kidney ultrastructure. PIC attenuated cisplatin-induced reduction in Nrf2 expression and the relative mRNA level of antioxidant enzymes: hemeoxygenase-1, cysteine ligase catalytic, and modifier subunits, as well as superoxide dismutase and glutathione-S-transferase activities. Cisplatin pro-inflammatory response was reduced by PIC treatment as evidenced by the suppression of nuclear factor kappa-B activation and the subsequent decreased tissue levels of interleukin-1β, tumor necrosis factor-α, cyclooxygenase-2, and inducible nitric oxide synthase. PIC suppressed cisplatin-induced apoptosis by decreasing p53 and cytochrome C expression and caspase-3 activity. Therefore, PIC may protect against cisplatin-induced nephrotoxicity by modulating Nrf2/HO-1 signaling and hindering the inflammatory and apoptotic pathways.

Keywords

Cisplatin Nephrotoxicity Inflammation Oxidative stress Piceatannol 

Abbreviations

GCLC

Glutamate cysteine ligase catalytic subunit

GCLM

Glutamate cysteine ligase modifier subunit

GST

Glutathione S transferase

HO-1

Hemeoxygenase-1

KIM-1

Kidney injury molecule 1

NGAL

Neutrophil gelatinase associated lipocalin

Nrf2

Nuclear factor E2-related factor 2

NF-κB

Nuclear factor kappa-B

OCT-2

Organic cation transporter 2

Notes

Acknowledgments

The authors would like to thank Dr. Ahmed Esmat, Associate Professor of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, for his cooperation in the Western blotting analysis.

Author contribution

SAW executed the experimental model and most of the experimental methods, analyzed the data, and wrote the first draft of the manuscript. SSA and DAE executed part of the experiments, analyzed the data, and wrote the final draft the manuscript draft. EE-D put the rational of the study, designed the experimental model, analyzed the data, and wrote the final draft of the manuscript.

Compliance with ethical standards

The study was approved by the ethical committee of Faculty of Pharmacy, Ain Shams University (Cairo, Egypt) (REC-ASU PhD No. 5).

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Pharmacology & Toxicology Department, Faculty of PharmacyAin Shams UniversityCairoEgypt

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