Perindopril regulates the inflammatory mediators, NF-κB/TNF-α/IL-6, and apoptosis in cisplatin-induced renal dysfunction
- 183 Downloads
Cisplatin (CP) is an essential chemotherapeutic drug used over the world against many types of cancer. It has several side effects such as ototoxicity, myelosuppression, and nephrotoxicity. Nephrotoxicity is the most dangerous and is considered a dose-limiting one. Oxidative stress, inflammation, and apoptosis are involved in this toxicity. This study was conducted to focus on the impact of perindopril (PER) against CP-induced nephrotoxicity in rat. Male albino rats were divided to control, rats received a single dose of CP, rats received PER, and rats co-received PER and CP. Nephrotoxicity evoked by CP challenge was characterized histologically and biochemically including significant increase in relative kidney/body weight ratio and serum urea and creatinine. Additionally, CP markedly increased renal tissue content of malondialdehyde (MDA) while decreased reduced glutathione (GSH) and depleted glutathione-S-transferase (GST) activity. CP produced significant increase in the inflammation biomarkers; nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), and interlukine-6 (IL-6). Administration of CP clearly upregulated caspase-3, while it downregulated B-cell lymphoma-2 (BCL-2) gene expressions. Perindopril treatment showed a significant restoration in the pathological alterations histologically and biochemically, which are provoked by CP administration. Altogether, these results suggested a good therapeutic role of PER against CP-induced nephrotoxicity through its influence on oxidative stress, inflammation, and apoptosis pathway.
KeywordsCisplatin Perindopril Nephrotoxicity Inflammation Apoptosis
The authors are grateful to Prof. Dr. Dr. Kawkab A. Ahmed, Professor of Pathology, Faculty of Veterinary Medicine, Cairo University, Egypt, for her kind help in performing the histopathological examination.
AS Shalkami and MIA Hassan conceived and designed this research. All the authors conducted experiments. AS Shalkami and AA Abd El-Ghany analyzed data. AS Shalkami and MIA Hassan wrote the manuscript. All the authors read and approved the manuscript.
Compliance with ethical standards
All animals’ procedures in this work were conducted according to the Animal Ethics Committee, Faculty of Medicine, Assiut University, Egypt.
Conflict of interest
The authors declare that they have no conflict of interest.
- Banchroft JD, Stevens A, Turner DR (1996) Theory and practice of histological techniques, 4th edn. Churchill Livingstone, New YorkGoogle Scholar
- Baradaran A, Tavafi M, Ardalan MR et al (2016) Cisplatin; nephrotoxicity and beyond. Ann Res Antioxidants 1:e014Google Scholar
- Darwish MA, Abo-Youssef AM, Khalaf MM, Abo-Saif AA, Saleh IG, Abdelghany TM (2017) Vitamin E mitigates cisplatin-induced nephrotoxicity due to reversal of oxidative/nitrosative stress, suppression of inflammation and reduction of total renal platinum accumulation. J Biochem Mol Toxicol 31:1–9. https://doi.org/10.1002/jbt.21833 CrossRefPubMedGoogle Scholar
- Hayati F, Hossainzadeh M, Shayanpour S et al (2016) Prevention of cisplatin nephrotoxicity. J Nephropharmacology 5:57Google Scholar
- Khan MAH, Sattar MA, Abdullah NA et al (2007) Cisplatin-induced nephrotoxicity causes altered renal hemodynamics in Wistar Kyoto and spontaneously hypertensive rats: role of augmented renal alpha-adrenergic responsiveness. Exp Toxicol Pathol 59:253–260. https://doi.org/10.1016/j.etp.2007.05.005 CrossRefGoogle Scholar
- Lee J, Nakagiri T, Oto T, Harada M, Morii E, Shintani Y, Inoue M, Iwakura Y, Miyoshi S, Okumura M, Hirano T, Murakami M (2012) IL-6 amplifier, NF-κB–triggered positive feedback for IL-6 signaling, in grafts is involved in allogeneic rejection responses. J Immunol 189:1928–1936. https://doi.org/10.4049/jimmunol.1103613 CrossRefPubMedGoogle Scholar
- Lowry OH, Rosebrough NJ, Farr AL et al (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275Google Scholar
- Ognjanović BI, Djordjević NZ, Matić MM, Obradović JM, Mladenović JM, Štajn AŠ, Saičić ZS (2012) Lipid peroxidative damage on cisplatin exposure and alterations in antioxidant defense system in rat kidneys: a possible protective effect of selenium. Int J Mol Sci 13:1790–1803. https://doi.org/10.3390/ijms13021790 CrossRefPubMedPubMedCentralGoogle Scholar