Piceatannol protects against cisplatin nephrotoxicity via activation of Nrf2/HO-1 pathway and hindering NF-κB inflammatory cascade
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.
KeywordsCisplatin Nephrotoxicity Inflammation Oxidative stress Piceatannol
Glutamate cysteine ligase catalytic subunit
Glutamate cysteine ligase modifier subunit
Glutathione S transferase
Kidney injury molecule 1
Neutrophil gelatinase associated lipocalin
Nuclear factor E2-related factor 2
Nuclear factor kappa-B
Organic cation transporter 2
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.
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 was obtained from all individual participants included in the study.
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