title: How does colistin-induced nephropathy develop and can it be treated?
abstract: Colistin is an old antibiotic used in the treatment of Gram-negative infections. It was once suspended because of its nephrotoxic effect but has since been reintroduced due to multidrug-resistant bacterial infections. The pathogenesis of colistin-associated nephropathy has not been clarified, and there is currently no effective therapeutic or prophylactic agent available. The aim of this study was to investigate the roles of caspase-associated apoptosis and caspase 1, calpain 1, inducible nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS) expression in the pathogenesis of colistin-associated nephrotoxicity and the effect of grape seed proanthocyanidin extract (GSPE) in preventing it. Twenty-four rats were divided into three groups: control, colistin, and colistin plus GSPE (colistin+GSPE). Colistin-associated nephropathy was induced by the administration of 300,000 IU/kg of body weight/day colistin intraperitoneally for 7 days. The experiment was discontinued on the seventh day. Blood was collected for measurements of blood urea nitrogen (BUN) and creatinine levels. Histopathological examination of kidney tissue and caspase 1 and 3, iNOS, eNOS, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL), and calpain 1 staining was also performed. Significant increases in BUN levels; creatinine levels; renal histopathological scores; and TUNEL, caspase 1 and 3, calpain 1, iNOS, and eNOS staining were observed for the colistin group compared to the control group. Significant decreases in BUN levels; creatinine levels; renal histopathological scores; and TUNEL, caspase 1 and 3, calpain 1, iNOS, and eNOS staining were observed in the colistin+GSPE group compared to the colistin group. Our study shows, for the first time in the literature, that caspase-mediated apoptosis, iNOS, caspase 1, and calpain 1 are involved in the pathogenesis of colistin-associated nephropathy. GSPE had a renoprotective effect, as shown by the lowered levels of these mediators.
authors: Department of Nephrology, Karadeniz Technical University, School of Medicine, Trabzon, Turkey. gulsumozkan78@hotmail.com
authors: Gulsum
authors: G
authors: Ozkan
authors: Sukru
authors: S
authors: Ulusoy
authors: Asim
authors: A
authors: Orem
authors: Mehmet
authors: M
authors: Alkanat
authors: Sevdegül
authors: S
authors: Mungan
authors: Esin
authors: E
authors: Yulug
authors: Fulya Balaban
authors: FB
authors: Yucesan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001806:Blood Urea Nitrogen; D002154:Calpain / Q000378:metabolism; D020169:Caspases / Q000097:blood; D003091:Colistin / Q000008:administration & dosage / Q000009:adverse effects*; D015971:Gene Expression Regulation, Enzymologic; D056604:Grape Seed Extract / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000188:drug therapy; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D008517:Phytotherapy; D044945:Proanthocyanidins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D027843:Vitis / Q000378:metabolism
chemical_list: D056604:Grape Seed Extract; C511402:Grape Seed Proanthocyanidins; D044945:Proanthocyanidins; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D002154:Calpain; C491071:Casp4 protein, rat; D020169:Caspases; D003091:Colistin
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