Ferulic Acid Ameliorates Chromium-Induced Nephrotoxicity: Modulation of PERK/eIF2α/ATF4/CHOP, Nrf2, and Inflammatory Signaling.

Hexavalent chromium (HVC) is a highly toxic heavy metal that induces organ damage especially to the kidney. It induces tubular damage and glomerular dysfunction basically through triggering inflammation, redox imbalance, and apoptotic cell death. The current study aimed at investigating the possible protective ability of ferulic acid (FA) against HVC-induced nephrotoxicity employing male Wistar rats as an experimental model. The results revealed the ability of FA to suppress the HVC-evoked renal tissue injury and to improve the renal function, as evidenced by enhanced histopathological picture, reduced levels of the tubular injury biomarker KIM- 1, and the glomerular dysfunction biomarkers serum cystatin C and urea, along with boosted glomerular filtration rate. At the molecular level, FA suppressed HVC-induced inflammation, as indicated by decreased nuclear NF-κB p65 protein abundance and phosphorylation, and reduced cyclooxygenase- 2, IL- 1β, and TNF-α levels. FA significantly alleviated the HVC-induced redox imbalance as demonstrated by reduced lipids and DNA oxidation, upregulation of Nrf2 signaling, improved activity of the antioxidant enzymes thioredoxin reductase, catalase, and glutathione peroxidase, along with significant elevation of the reduced glutathione level. FA inhibited apoptosis in the HVC-intoxicated rats as evidenced by reduced activity of the apoptotic marker caspase- 3 and modulation of BAX and Bcl2 proteins. Interestingly, FA suppressed the unfolded protein response signaling molecules including PERK, eIF2α, ATF4, and CHOP, which play essential roles in induction of apoptosis and inflammation. Together, these results underscore the nephroprotective impact of FA against HVC-evoked nephrotoxicity and highlight PERK, eIF2α, ATF4, CHOP, Nrf2, and NF-κB as potential molecular targets.