Nevertyty M Mahmoud1, Shimaa M Elshazly2, Samar Rezq3. 1. Department of Pharmacology, Faculty of Medicine, Zagazig University, Zagazig 4115, Egypt. 2. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, 4115, Egypt. 3. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, 4115, Egypt. Electronic address: srezq@umc.edu.
Abstract
AIMS: The nephrotoxicity of cyclosporine A (CsA) limits its use as an immunosuppressant. Wnt/β-catenin signaling is involved in the pathogenesis of both acute and chronic kidney disease, and it is inhibited by peroxisome proliferator-activated receptor gamma (PPARγ). We aimed to evaluate if geraniol, which can modulate both PPARγ and Wnt signaling, could protect against CsA-induced nephrotoxicity. MATERIALS AND METHODS: Rats (6 groups) received the vehicle or a combination of CsA (30 mg/kg) with the vehicle, geraniol (50, 100, or 200 mg/kg), or the PPARγ agonist pioglitazone for 4 weeks. Blood pressure (BP), markers of renal injury (serum urea, serum creatinine, blood urea nitrogen, and urinary NAG), oxidative stress (glutathione peroxidase), inflammation (ICAM-1, IL-18, and NF-κB), apoptosis (caspase-3), extracellular matrix remodeling [matrix metalloproteinase-9 (MMP-9)], and fibrosis (TGF-β1, Smad3, and Smad7) were assessed. Renal histological analysis, Wnt signaling components (Wnt-4/β-catenin and E-cadherin), and PPARγ expression were evaluated. KEY FINDINGS: CsA group had renal injury, as well as increased BP, renal oxidative stress, inflammation, and fibrosis. The latter changes were associated with altered renal architecture, active Wnt signaling (higher Wnt-4 and β-catenin expression and E-cadherin down-regulation), and lower PPARγ levels. Geraniol protected against kidney damage and the associated biochemical and histomorphological changes in a dose-dependent manner. The latter effects were comparable or superior to those of pioglitazone. SIGNIFICANCE: The down-regulation of Wnt/β-catenin and the increase in PPARγ by geraniol suggest that both pathways are involved in its renoprotective potential. The study highlights geraniol as a valuable protective asset against chemically induced nephrotoxicity.
AIMS: The nephrotoxicity of cyclosporine A (CsA) limits its use as an immunosuppressant. Wnt/β-catenin signaling is involved in the pathogenesis of both acute and chronic kidney disease, and it is inhibited by peroxisome proliferator-activated receptor gamma (PPARγ). We aimed to evaluate if geraniol, which can modulate both PPARγ and Wnt signaling, could protect against CsA-induced nephrotoxicity. MATERIALS AND METHODS: Rats (6 groups) received the vehicle or a combination of CsA (30 mg/kg) with the vehicle, geraniol (50, 100, or 200 mg/kg), or the PPARγ agonist pioglitazone for 4 weeks. Blood pressure (BP), markers of renal injury (serum urea, serum creatinine, blood urea nitrogen, and urinary NAG), oxidative stress (glutathione peroxidase), inflammation (ICAM-1, IL-18, and NF-κB), apoptosis (caspase-3), extracellular matrix remodeling [matrix metalloproteinase-9 (MMP-9)], and fibrosis (TGF-β1, Smad3, and Smad7) were assessed. Renal histological analysis, Wnt signaling components (Wnt-4/β-catenin and E-cadherin), and PPARγ expression were evaluated. KEY FINDINGS: CsA group had renal injury, as well as increased BP, renal oxidative stress, inflammation, and fibrosis. The latter changes were associated with altered renal architecture, active Wnt signaling (higher Wnt-4 and β-catenin expression and E-cadherin down-regulation), and lower PPARγ levels. Geraniol protected against kidney damage and the associated biochemical and histomorphological changes in a dose-dependent manner. The latter effects were comparable or superior to those of pioglitazone. SIGNIFICANCE: The down-regulation of Wnt/β-catenin and the increase in PPARγ by geraniol suggest that both pathways are involved in its renoprotective potential. The study highlights geraniol as a valuable protective asset against chemically induced nephrotoxicity.
Authors: Eman M El-Mancy; Dalia Mahmoud Abdelmonem Elsherbini; Rasha Hamed Al-Serwi; Mohamed El-Sherbiny; Gehan Ahmed Shaker; Abdel-Moneim Hafez Abdel-Moneim; Eman T Enan; Nehal M Elsherbiny Journal: Toxics Date: 2022-08-02