Imperatorin ameliorates renal damage and modulates MAPK, Nrf2, and NF-kB pathways in mercury-chloride-exposed rats: A toxicological study relevant to skin lightening practices.

BACKGROUND: A major global public health concern is the widespread and illegal use of mercury compounds in skin-lightening cosmetics, mainly because of their extreme systemic toxicity, especially to the kidneys. Imperatorin is a promising natural furanocoumarin compound with high antioxidant properties. This study investigates the mechanism of mercury-induced nephrotoxicity and the curative properties of imperatorin, focusing on the NF-κB, MAPKs, and Nrf2 signalling pathways. METHODS: Rats were divided into control, mercury-chloride (HgCl2)-treated (2.5 mg/kg), imperatorin-treated (15 mg/kg), and two co-treated groups receiving HgCl2 (2.5 mg/kg) with either 10 mg/kg or 15 mg/kg of imperatorin. Our study examined tissue histopathology, renal function markers, oxidative stress parameters, inflammatory cytokines, as well as the expression of nephrin, podocin, Kidney Injury Marker-1 (KIM-1), Nrf2, NF-kB, p38, ERK, and JNK mRNA levels. Further, the activated protein levels of p38, ERK and JNK were confirmed using a western blot. RESULTS: Imperatorin decreased the levels of creatinine, urea, and uric acid; increased protein and albumin levels and restored pathological changes in a dose-dependent manner. The antioxidant levels of superoxide dismutase, reduced glutathione, glutathione peroxidase and catalase were also restored by imperatorin treatment while modulating the levels of ROS, MDA, TNF-α, IL-6 and IL-1β. Gene expression analysis showed a significant increase in KIM-1 and a decrease in nephrin and podocin levels in the HgCl2 group, suggesting kidney injury. Imperatorin modulated the gene expression levels of MAPKs (p38, Erk, and Jnk), Nrf2, and NF-κB in the HgCl2 groups. Protein expression levels of MAPKs confirmed that MAPK signal activation in the HgCl2 group decreased by imperatorin treatment. CONCLUSION: These results show that in an in vivo model, imperatorin provides significant protection against HgCl2-induced nephrotoxicity.