Geraniol Averts Methotrexate-Induced Acute Kidney Injury via Keap1/Nrf2/HO-1 and MAPK/NF-κB Pathways

• Published in: Current issues in molecular biology Vol. 43; no. 3; pp. 1741 - 1755
• Main Authors: Younis, Nancy S., Elsewedy, Heba S., Shehata, Tamer M., Mohamed, Maged E.
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 24.10.2021; MDPI AG
• Subjects: Acute Kidney Injury - drug therapy; Acute Kidney Injury - etiology; Acute Kidney Injury - metabolism; Acute Kidney Injury - pathology; Acyclic Monoterpenes - pharmacology; Animals; apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Biomarkers; Biopsy; Disease Management; Disease Susceptibility; essential oil; Heme Oxygenase (Decyclizing) - metabolism; inflammatory mediators; Kelch-Like ECH-Associated Protein 1 - metabolism; Male; Methotrexate - adverse effects; Mitogen-Activated Protein Kinases - metabolism; monoterpene; NF-E2-Related Factor 2 - metabolism; NF-kappa B - metabolism; Oxidative Stress; Protective Agents - pharmacology; Rats; Reactive Oxygen Species - metabolism; renal injury; Signal Transduction - drug effects; inflammatory mediators; apoptosis; monoterpene; essential oil; renal injury
• ISSN: 1467-3045; 1467-3037; 1467-3045
• DOI: 10.3390/cimb43030123

Objectives: Geraniol, a natural monoterpene, is an essential oil component of many plants. Methotrexate is an anti-metabolite drug, used for cancer and autoimmune conditions; however, clinical uses of methotrexate are limited by its concomitant renal injury. This study investigated the efficacy of geraniol to prevent methotrexate-induced acute kidney injury and via scrutinizing the Keap1/Nrf2/HO-1, P38MAPK/NF-κB and Bax/Bcl2/caspase-3 and -9 pathways. Methods: Male Wister rats were allocated into five groups: control, geraniol (orally), methotrexate (IP), methotrexate and geraniol (100 and 200 mg/kg). Results: Geraniol effectively reduced the serum levels of creatinine, urea and Kim-1 with an increase in the serum level of albumin when compared to the methotrexate-treated group. Geraniol reduced Keap1, escalated Nrf2 and HO-1, enhanced the antioxidant parameters GSH, SOD, CAT and GSHPx and reduced MDA and NO. Geraniol decreased renal P38 MAPK and NF-κB and ameliorated the inflammatory mediators TNF-α, IL-1β, IL-6 and IL-10. Geraniol negatively regulated the apoptotic mediators Bax and caspase-3 and -9 and increased Bcl2. All the biochemical findings were supported by the alleviation of histopathological changes in kidney tissues. Conclusion: The current findings support that co-administration of geraniol with methotrexate may attenuate methotrexate-induced acute kidney injury.