Protective effects of quercetin against glyphosate-induced nephrotoxicity in rats: role of oxidative stress, inflammatory response, and apoptotic pathways.

Background: Glyphosate, the most widely used herbicide globally, accumulates in renal tissue causing kidney damage through incompletely understood mechanisms. This study evaluated quercetin's nephroprotective effect against glyphosate-induced kidney injury in rats.

Methods: Five groups of male Wistar rats (n = 10 each) received daily treatments for 21 days: control, glyphosate (25 mg/kg), quercetin (50 mg/kg), and quercetin+glyphosate at low (25 mg/kg) or high (50 mg/kg) doses. All treatments were administered by oral gavage for 21 days. Renal parameters, oxidative stress markers, inflammatory mediators, and apoptotic indicators were assessed using spectrophotometric assays, ELISA, qRT-PCR, and histology.

Results: Glyphosate impaired renal function, increased kidney weight, and elevated kidney injury molecule-1 (KIM-1) levels. It suppressed antioxidant enzymes (CAT, SOD, GPX) and downregulated their mRNA expression (Cat, Sod2, and Gpx-1, respectively), while depleting GSH and increasing oxidative markers (MDA, NO). Notably, glyphosate reduced Nrf2 protein and Nfe2l2 gene expression, disrupting this master regulator of antioxidant responses, with concurrent Hmox-1 downregulation. Glyphosate upregulated pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), increased TLR-4 and NOS2 expression, activated mitochondrial apoptosis by increasing pro-apoptotic proteins (BAX, CYTOCHROME C, and CASPASE-3) while decreasing anti-apoptotic BCL-2 protein levels, with corresponding changes in gene expression. Consistent with protein findings, Bcl-2 gene expression was significantly downregulated, further confirming the shift toward pro-apoptotic signaling. Quercetin dose-dependently attenuated these alterations, with high-dose providing superior protection compared to low-dose by restoring gene expression and enzyme activities. Histopathological examination confirmed quercetin mitigated glyphosate-induced tubular degeneration and glomerular atrophy.

Conclusion: Quercetin protects against glyphosate nephrotoxicity through antioxidative, anti-inflammatory, and anti-apoptotic mechanisms, suggesting therapeutic potential against herbicide-induced kidney injury.