Losartan prevents methotrexate-induced liver and lung injury in rats via targeting PPAR-γ/TGF-β1/SMAD3 and Nrf2/redox signaling | ||||
| Zagazig University Medical Journal | ||||
| Article 17, Volume 29, Issue 1, January 2023, Page 135-148 PDF (1.4 MB) | ||||
| Document Type: Original Article | ||||
| DOI: 10.21608/zumj.2022.173474.2682 | ||||
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| Authors | ||||
Noha A.T. Abbas1; Shaimaa S. El-Sayed 2; Samaa Salah Abd El-Fatah 3; Walaa M. Sarhan4; Omnia Sarhan5; Eman M. A. Abdelghany6; Shireen S. Mahmoud  1
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| 1Department of Clinical Pharmacology, Faculty of Medicine, Zagazig University, Zagazig, Egypt. | ||||
| 2Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt. | ||||
| 3Department of Human Anatomy and Embryology, Faculty of Medicine, Zagazig University, Zagazig, Egypt. | ||||
| 4Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Zagazig University, Zagazig, Egypt. Wake Forest Institute of Regenerative Medicine (WFIRM), NC, USA. | ||||
| 5Department of Pharmaceutics, Faculty of Pharmacy, Badr university, Cairo, Egypt. | ||||
| 6Department of Human Anatomy and Embryology, Faculty of Medicine, Zagazig University, Zagazig, Egypt | ||||
| Abstract | ||||
| Background: Despite high efficacy-to-toxicity ratio of chemotherapeutic agent, methotrexate, toxicity remains a major concern that limits its use. Inflammatory, oxidative stress and fibrotic pathways are implicated in methotrexate-induced injury. This study aims to investigate the ability of losartan to limit methotrexate-induced liver and lung injury and to elucidate the possible underlying mechanisms. Methods: Liver and lung injury was induced in adult male Wistar rats via methotrexate ip injection twice weekly for 4weeks (0.5mg/kg), animals were divided into group1 (control) where rats received saline ip twice weekly with daily vehicles for 4weeks; group 2 to 4 included rats treated with methotrexate and began to receive drugs or vehicles concurrently, where in group2 rats received vehicles daily, whereas in group3 rats received losartan at 10mg/kg/day by gavage and those of group4 received both losartan and bisphenol-A-diglycidyl ether (BADGE, 30mg/kg). Circulating liver enzymes, histological examination of liver and lung as well as peroxisome proliferator-activated receptor-γ (PPAR-γ)/transforming growth factor-β (TGF-β)/SMAD3 and nuclear factor (erythroid-derived2)-like2 (Nrf2)/antioxidants pathways were investigated. Results: Losartan ameliorated methotrexate-induced hepatic and pulmonary injury manifested by improved circulating liver enzymes, restoration of normal liver and lung histology, upregulated PPAR-γ, suppressed TGF-β/SMAD3 signaling while activated Nrf2-mediated antioxidant defenses and reduced lipid peroxidation biomarker malondialdehyde. Losartan effects were abrogated on concurrent use of BADGE, a selective PPAR-γ antagonist. Conclusions: Losartan’s antifibrotic effect via suppression of TGF-β/SMAD3 profibrotic signaling and antioxidant potentials through activation of Nrf2/antioxidant pathway are more likely attributed to PPAR-γ induction. This suggests the usefulness of losartan in limiting methotrexate-associated multiorgan injury. | ||||
| Keywords | ||||
| Methotrexate; liver injury; lung injury; losartan; PPAR-γ | ||||
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