title: Baicalein, a Bioflavonoid, Prevents Cisplatin-Induced Acute Kidney Injury by Up-Regulating Antioxidant Defenses and Down-Regulating the MAPKs and NF-κB Pathways.
abstract: Acute renal failure is a serious complication of the anticancer drug cisplatin. The potential role of baicalein, a naturally occurring bioflavonoid on cisplatin-induced renal injury is unknown. Here, we assessed the effect of baicalein against a murine model of cisplatin-induced acute renal failure and investigated the underlying possible mechanisms. Renal function, kidney histology, inflammation, oxidative stress, renal mitochondrial function, proteins involved in apoptosis, nuclear translocation of Nrf2 and effects on intracellular signaling pathways such as MAPKs, and NF-κB were assessed. Pretreatment with baicalein ameliorated the cisplatin-induced renal oxidative stress, apoptosis and inflammation and improved kidney injury and function. Baicalein inhibited the cisplatin-induced expression of iNOS, TNF-α, IL-6 and mononuclear cell infiltration and concealed redox-sensitive transcription factor NF-κB activation via reduced DNA-binding activity, IκBα phosphorylation and p65 nuclear translocation in kidneys. Further studies demonstrated baicalein markedly attenuated cisplatin-induced p38 MAPK, ERK1/2 and JNK phosphorylation in kidneys. Baicalein also restored the renal antioxidants and increased the amount of total and nuclear accumulation of Nrf2 and downstream target protein, HO-1 in kidneys. Moreover, baicalein preserved mitochondrial respiratory enzyme activities and inhibited cisplatin-induced apoptosis by suppressing p53 expression, Bax/Bcl-2 imbalance, cytochrome c release and activation of caspase-9, caspase-3 and PARP. Our findings suggest that baicalein ameliorates cisplatin-induced renal damage through up-regulation of antioxidant defense mechanisms and down regulation of the MAPKs and NF-κB signaling pathways.
authors.affiliation: Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, 500 007, India.
authors.forename: Bidya Dhar
authors.initials: BD
authors.lastname: Sahu
authors.affiliation: Animal House Facility, CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad, 500 007, India.
authors.forename: Jerald
authors.initials: J
authors.lastname: Mahesh Kumar
authors.affiliation: Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, 500 007, India.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Sistla
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D002945:Cisplatin / Q000009:adverse effects; D015536:Down-Regulation / Q000187:drug effects*; D044950:Flavanones / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D044950:Flavanones; D005419:Flavonoids; D016328:NF-kappa B; C006680:baicalein; D020928:Mitogen-Activated Protein Kinases; D002945:Cisplatin