title: Naringin ameliorates gentamicin-induced nephrotoxicity and associated mitochondrial dysfunction, apoptosis and inflammation in rats: possible mechanism of nephroprotection.
abstract: Gentamicin-induced nephrotoxicity has been well documented, although its underlying mechanisms and preventive strategies remain to be investigated. The present study was designed to investigate the protective effect of naringin, a bioflavonoid, on gentamicin-induced nephrotoxicity and to elucidate the potential mechanism. Serum specific renal function parameters (blood urea nitrogen and creatinine) and histopathology of kidney tissues were evaluated to assess the gentamicin-induced nephrotoxicity. Renal oxidative stress (lipid peroxidation, protein carbonylation, enzymatic and non-enzymatic antioxidants), inflammatory (NF-kB [p65], TNF-α, IL-6 and MPO) and apoptotic (caspase 3, caspase 9, Bax, Bcl-2, p53 and DNA fragmentation) markers were also evaluated. Significant decrease in mitochondrial NADH dehydrogenase, succinate dehydrogenase, cytochrome c oxidase and mitochondrial redox activity indicated the gentamicin-induced mitochondrial dysfunction. Naringin (100mg/kg) treatment along with gentamicin restored the mitochondrial function and increased the renal endogenous antioxidant status. Gentamicin induced increased renal inflammatory cytokines (TNF-α and IL-6), nuclear protein expression of NF-κB (p65) and NF-κB-DNA binding activity and myeloperoxidase (MPO) activity were significantly decreased upon naringin treatment. In addition, naringin treatment significantly decreased the amount of cleaved caspase 3, Bax, and p53 protein expression and increased the Bcl-2 protein expression. Naringin treatment also ameliorated the extent of histologic injury and reduced inflammatory infiltration in renal tubules. U-HPLS-MS data revealed that naringin co-administration along with gentamicin did not alter the renal uptake and/or accumulation of gentamicin in kidney tissues. These findings suggest that naringin treatment attenuates renal dysfunction and structural damage through the reduction of oxidative stress, mitochondrial dysfunction, inflammation and apoptosis in the kidney.
authors.affiliation: Medicinal Chemistry and Pharmacology Division, Indian Institute of Chemical Technology (IICT), Hyderabad 500 007, India.
authors.forename: Bidya Dhar
authors.initials: BD
authors.lastname: Sahu
authors.affiliation: National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
authors.forename: Srujana
authors.initials: S
authors.lastname: Tatireddy
authors.affiliation: Medicinal Chemistry and Pharmacology Division, Indian Institute of Chemical Technology (IICT), Hyderabad 500 007, India.
authors.forename: Meghana
authors.initials: M
authors.lastname: Koneru
authors.affiliation: National Centre for Mass Spectrometry, Indian Institute of Chemical Technology (IICT), Hyderabad 500 007, India.
authors.forename: Roshan M
authors.initials: RM
authors.lastname: Borkar
authors.affiliation: CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad 500 007, India.
authors.forename: Jerald Mahesh
authors.initials: JM
authors.lastname: Kumar
authors.affiliation: Medicinal Chemistry and Pharmacology Division, Indian Institute of Chemical Technology (IICT), Hyderabad 500 007, India.
authors.forename: Madhusudana
authors.initials: M
authors.lastname: Kuncha
authors.affiliation: National Centre for Mass Spectrometry, Indian Institute of Chemical Technology (IICT), Hyderabad 500 007, India.
authors.forename: R
authors.initials: R
authors.lastname: Srinivas
authors.affiliation: Faculty of Pharmacy, Osmania University, Hyderabad 500 007, India.
authors.forename: R
authors.initials: R
authors.lastname: Shyam Sunder
authors.affiliation: Medicinal Chemistry and Pharmacology Division, Indian Institute of Chemical Technology (IICT), Hyderabad 500 007, India. Electronic address: sistla@iict.res.in.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Sistla
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D044950:Flavanones / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D005839:Gentamicins / Q000494:pharmacology / Q000633:toxicity*; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000187:drug effects*; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D044950:Flavanones; D005419:Flavonoids; D005839:Gentamicins; D018836:Inflammation Mediators; D003404:Creatinine; C005274:naringin
keywords: Apoptosis; Gentamicin-induced nephrotoxicity; Inflammation; Mitochondrial dysfunction; Naringin