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Possible involvement of the lipoxygenase and leukotriene signaling pathways in cisplatin-mediated renal toxicity

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Abstract

Purpose

The present study examined the possible involvement of the lipoxygenase (LOX) pathway in cisplatin (CPT)-induced nephrotoxicity.

Methods

Wistar albino rats were challenged with CPT IP injection (7.5 mg/kg) and were sacrificed after one week. Signs of renal dysfunction, including urea and creatinine clearance levels and renal histological structure, were investigated. Gene and protein expression levels of different LOX pathway enzymes and products, including 5-LOX, 12-LOX, 15-LOX, 5-LOX activating protein (FLAP), leukotriene A4 hydrolase (LTA4 hydrolase), leukotriene C4 synthase (LTC4 synthase), LTB4 receptor, and cysteinyl (cys) LT receptor types 1 and 2, were also determined in the kidneys using real-time PCR and western blotting, respectively. The serum and kidney levels of LTB4 and inflammatory markers were also estimated.

Results

CPT renal toxicity was established as the creatinine and urea clearance levels were significantly reduced, while the serum levels of creatinine and urea were markedly increased. We reported a considerable up-regulation in the mRNA and protein expression levels of 5-LOX, FLAP, 12-LOX, LTA4 hydrolase, LTC4 synthase, LTB4 receptor, and Cys LT receptor types 1 and 2, while 15-LOX expression did not significantly change in the CPT group. Additionally, LTB4 and inflammatory indicators in serum and renal levels were elevated significantly in the CPT group. Histopathological examination clearly showed the nephrotoxic changes in the renal tissues of CPT-challenged animals.

Conclusions

Our findings suggested, for the first time, the participation of LOX enzymes and products in the signaling pathway leading to CPT-associated nephrotoxicity, which could be the foundation stone for combining LOX pathway attenuators with CPT therapy to decrease CPT-associated renal toxicity.

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Acknowledgements

This project was funded by the National Plane for Science, Technology and Innovation (MAARIFAH)-King Abdulaziz City for Science and Technology-the Kingdome of Saudi Arabia, Award Number (MED894-08-13).

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Authors and Affiliations

  1. Department of Pharmacology, College of Medicine, Al Imam Mohammad Ibn Saud Islamic University (IMSIU), P.O. Box 11623, Riyadh, 11544, Saudi Arabia

    Osama A. Alkhamees

  2. Department of Dermatology and Venereology, College of Medicine, Al Imam Mohammad Ibn Saud Islamic University (IMSIU), P.O. Box 11623, Riyadh, 11544, Saudi Arabia

    Abdulaziz S. Alroujayee

  3. Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11544, Saudi Arabia

    Hatem M. Abuohashish & Mohammed M. Ahmed

  4. Department of Biomedical Dental Sciences, College of Dentistry, University of Dammam, Dammam, 31441, Saudi Arabia

    Hatem M. Abuohashish

  5. Medical School, Al Maareefa Colleges, Riyadh, 11544, Saudi Arabia

    Fatima S. Alrojayee

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  1. Osama A. Alkhamees
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  2. Abdulaziz S. Alroujayee
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Correspondence to Osama A. Alkhamees.

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Alkhamees, O.A., Alroujayee, A.S., Abuohashish, H.M. et al. Possible involvement of the lipoxygenase and leukotriene signaling pathways in cisplatin-mediated renal toxicity. Cancer Chemother Pharmacol 80, 55–64 (2017). https://doi.org/10.1007/s00280-017-3331-8

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  • DOI: https://doi.org/10.1007/s00280-017-3331-8

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