title: Transcriptomic analysis of nephrotoxicity induced by cephaloridine, a representative cephalosporin antibiotic.
abstract: Cephaloridine (CER) is a classical beta-lactam antibiotic that has long served as a model drug for the study of cephalosporin antibiotic-induced acute tubular necrosis. In the present study, we analyzed gene expression profiles in the kidney of rats given subtoxic and toxic doses of CER to identify gene expression alterations closely associated with CER-induced nephrotoxicity. Male Fischer 344 rats were intravenously injected with CER at three different dose levels (150, 300, and 600 mg/kg) and sacrificed after 24 h. Only the high dose (600 mg/kg) caused mild proximal tubular necrosis and slight renal dysfunction. Microarray analysis identified hundreds of genes differentially expressed in the renal cortex following CER exposure, which could be classified into two main groups that were deregulated in dose-dependent and high dose-specific manners. The genes upregulated dose dependently mainly included those involved in detoxification and antioxidant defense, which was considered to be associated with CER-induced oxidative stress. In contrast, the genes showing high dose-specific (lesion-specific) induction included a number of genes related to cell proliferation, which appeared to reflect a compensatory response to CER injury. Of the genes modulated in both manners, we found many genes reported to be associated with renal toxicity by other nephrotoxicants. We could also predict potential transcription regulators responsible for the observed gene expression alterations, such as Nrf2 and the E2F family. Among the candidate gene biomarkers, kidney injury molecule 1 was markedly upregulated at the mildly toxic dose, suggesting that this gene can be used as an early and sensitive indicator for cephalosporin nephrotoxicity. In conclusion, our transcriptomic data revealed several characteristic expression patterns of genes associated with specific cellular processes, including oxidative stress response and proliferative response, upon exposure to CER, which may enhance our understanding of the molecular mechanisms behind cephalosporin antibiotic-induced nephrotoxicity.
authors.affiliation: Discovery Research Laboratories, Shionogi & Co., Ltd., 12-4, Sagisu 5-chome, Fukushima-ku, Osaka 553-0002, Japan. masatomo.rokushima@shionogi.co.jp
authors.forename: Masatomo
authors.initials: M
authors.lastname: Rokushima
authors.forename: Kae
authors.initials: K
authors.lastname: Fujisawa
authors.forename: Naoko
authors.initials: N
authors.lastname: Furukawa
authors.forename: Fumio
authors.initials: F
authors.lastname: Itoh
authors.forename: Toru
authors.initials: T
authors.lastname: Yanagimoto
authors.forename: Ryou
authors.initials: R
authors.lastname: Fukushima
authors.forename: Akiko
authors.initials: A
authors.lastname: Araki
authors.forename: Manabu
authors.initials: M
authors.lastname: Okada
authors.forename: Mikinori
authors.initials: M
authors.lastname: Torii
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kato
authors.forename: Jun
authors.initials: J
authors.lastname: Ishizaki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Omi
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D002509:Cephaloridine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D020869:Gene Expression Profiling; D005819:Genetic Markers; D008297:Male; D009401:Nephrosis / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D000900:Anti-Bacterial Agents; D005819:Genetic Markers; D002509:Cephaloridine