“Modulating Cadmium Chloride-Induced Hepatorenal Damage: Interplay of Trans-Resveratrol and Gamma Irradiation on Wnt/β-Catenin/NOTCH and NF-κB Signaling Axes”

Abstract

Cadmium chloride (CdCl₂) is a powerful environmental toxin that has been documented to induce severe hepatic and renal damage through oxidative stress mechanisms. This study evaluated the protective impact of combined low dose of gamma irradiation (LDR) and trans-resveratrol (Trans-Res) on CdCl₂-induced hepato-renal toxicity in rats. Five groups of 50 male albino rats had been classified as; control, CdCl₂ (2 mg/kg), CdCl₂+LDR (0.75 Gray), CdCl₂+Trans-Res (20 mg/kg/b.wt.), and CdCl₂+Trans-Res+LDR for 6 weeks. CdCl₂ significantly increased the enzymes of liver (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP]) and kidney markers (creatinine, urea), raised oxidative stress levels (hydrogen peroxide [H₂O₂], inducible nitric oxide synthase [iNOS]), lowered antioxidant activity superoxide dismutase (SOD), and increased fat breakdown products malondialdehyde (MDA) while causing inflammation (interleukin-6 [IL-6], nuclear factor kappa B [NF-κB]). Molecular analysis revealed that CdCl₂ downregulated Notch receptor 1 (Notch1) and Beta-catenin (β-catenin) genes with Wingless-related integration site (Wnt) protein and upregulated Axis inhibition protein 2 (Axin2), Cellular myelocytomatosis oncogene (c-myc), and Cyclin D genes with glycogen synthase kinase-3 beta (GSK-3β) and Hairy and enhancer of split 1 (HES1) proteins. Combined Trans-Res+LDR treatment significantly reduced these biochemical alterations, controlled gene expression levels, and enhanced histopathological alterations in the kidney and liver tissues. In conclusion, our findings evidently indicate that trans-resveratrol combined with low-dose of gamma irradiation provides powerful protective effects against CdCl₂-induced hepato-renal injuries through redox homeostasis recovery, suppression of inflammatory mediators, and modulation of apoptotic signaling pathways, which suggest a new therapeutic approach against the toxicity of CdCl₂ heavy metal.