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Alleviating effects of baicalein on nickel-induced nephrotoxicity: Modulation of FOXO3a, PGC1-α/MFN2/DRP1 signaling
Samir A Salama1, Mohamed A M Ali2, Afnan Bakhsh3
1Division of Biochemistry, Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
Background:
Despite its extensive industrial utility, nickel poses considerable health hazards to humans, in particular nephrotoxicity. The purpose of the present work was to assess the ability of baicalein to counteract the nickel-evoked nephrotoxicity.
Methods:
Male Wistar rats were subjected to nickel intoxication and concomitantly treated with baicalein for three weeks. Blood and kidney samples were collected for analyses using histopathology, ELISA, biochemical, and Western blotting techniques.
Results:
Baicalein treatment notably improved the kidney function in the nickel-exposed rats as demonstrated by enhanced glomerular filtration, reduced serum levels of urea and creatinine, decreased urinary albumin/creatinine ratio, downregulation of the renal tubular injury marker lipocalin-2, and enhanced renal histopathology. At the molecular level, baicalein boosted the mitochondrial dynamics as reflected by upregulation of PGC-1α and MFN2 protein levels, concurrently with downregulation of DRP1. Baicalein suppressed the nickel-induced apoptosis as indicated by effective reduction in BAX/Bcl2 protein ratio and suppression of caspase-3 activity. Interestingly, baicalein enhanced the transcriptional activity of FOXO3a and activity of its target enzymes catalase, thioredoxin reductase, and SOD, and suppressed oxidative modification of DNA and lipids. Additionally, it curbed NF-κB nuclear accumulation and levels of its responsive inflammatory cytokines IL-1β and TNF-α, whereas it boosted the anti-inflammatory IL-10.
Conclusion:
Collectively, these findings demonstrate that baicalein alleviates nickel-induced nephrotoxicity, an effect associated with modulation of PGC1-α/MFN2/DRP1, FOXO3a, NF-κB, and the intrinsic apoptotic signaling pathway.
