Chrysin Mitigates Chromium-Induced Nephrotoxicity Via Modulation of AMPK/SIRT1/NF-κB/p53 Signaling Cascade and PGC-1α...

Hexavalent chromium [Cr(VI)] is a hazardous heavy metal that poses serious toxicity to humans, in particular nephrotoxicity. The current work explored the potential nephroprotective impact of chrysin against Cr(VI)-induced nephrotoxicity. Chrysin significantly improved renal functions in the Cr(VI)-treated rats as indicated by decreased levels of urinary protein loss, serum creatinine and urea, and renal lipocalin-2, together with improved renal histopathological picture. Mechanistically, chrysin upregulated AMPK signaling as evidenced by a significant increase in phospho-AMPK and its downstream target SIRT1. These findings were accompanied by a significant decrease in the acetylated (active) forms of NF-κB and p53 the transcription factors that control inflammation and apoptosis. Additionally, chrysin inhibited NF-κB nuclear translocation, increased level of its cytosolic inhibitory protein IκB, and reduced levels of its responsive inflammatory molecules interleukin-6 and cyclooxygenase-2. Moreover, it modulated levels of p53-responsive apoptotic proteins BAX and Bcl2. Interestingly, chrysin boosted the master regulator of mitochondrial biogenesis PGC-1α, modulated its responsive proteins DRP1 and MFN2, increased activity of the antioxidant enzymes catalase and thioredoxin reductase, together with inhibition of lipid hydroperoxidation and DNA oxidation. Collectively, these findings highlight the mitigating activity of chrysin against Cr(VI)-induced nephrotoxicity and underscore AMPK, SIRT1, NF-κB, p53, and PGC-1α as underlying molecular targets.