Abstract

Nephrotoxicity is an important adverse effect of oxidative stress induced by hexavalent chromium [Cr(VI)]. The effect of ellagic acid, a dietary polyphenolic compound with potent antioxidant activity, was investigated in Cr(VI)-induced kidney injury. Six groups of male Wistar rats were treated intragastrically with vehicle or ellagic acid (15 and 30 mg/kg) for 10 days. On day 10, rats received saline or Cr(VI) (K2Cr2O7 15 mg/kg) subcutaneously. Cr(VI) significantly increased kidney weight, affected kidney function assessed by biomarkers in blood and urine (protein, creatinine and urea nitrogen), caused histological changes (tubular injury and glomerular capillary tuft damage), increased markers of oxidative stress and reduced the activity of antioxidant enzymes. In addition, Cr(VI) altered mitochondrial ultrastructure, impaired mitochondrial respiration, increased lipid peroxidation, and inhibited the function of mitochondrial enzymes. Pretreatment with ellagic acid (30 mg/kg) attenuated all the aforementioned alterations. Furthermore, we explored whether ellagic acid might regulate the tumor necrosis factor-alpha (TNF-α)/receptor-interacting protein kinase 3 (RIPK3) pathway, reducing Cr(VI)-induced tubular necrosis. Cr(VI) upregulated both TNF-α and RIPK3, but ellagic acid only decreased TNF-α levels, having no effect on RIPK3 content. Therefore, understanding the mechanisms through which Cr(VI) promotes necroptosis is crucial for future studies, in order to design strategies to mitigate kidney damage. In conclusion, ellagic acid attenuated Cr(VI)-induced renal alterations by preventing oxidative stress, supporting enzymatic activities, suppressing TNF-α, and preserving mitochondrial ultrastructure and function, most likely due to its antioxidant properties.

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