title: Identification of putative gene based markers of renal toxicity.
abstract: This study, designed and conducted as part of the International Life Sciences Institute working group on the Application of Genomics and Proteomics, examined the changes in the expression profile of genes associated with the administration of three different nephrotoxicants--cisplatin, gentamicin, and puromycin--to assess the usefulness of microarrays in the understanding of mechanism(s) of nephrotoxicity. Male Sprague-Dawley rats were treated with daily doses of puromycin (5-20 mg/kg/day for 21 days), gentamicin (2-240 mg/kg/day for 7 days), or a single dose of cisplatin (0.1-5 mg/kg). Groups of rats were sacrificed at various times after administration of these compounds for standard clinical chemistry, urine analysis, and histological evaluation of the kidney. RNA was extracted from the kidney for microarray analysis. Principal component analysis and gene expression-based clustering of compound effects confirmed sample separation based on dose, time, and degree of renal toxicity. In addition, analysis of the profile components revealed some novel changes in the expression of genes that appeared to be associated with injury in specific portions of the nephron and reflected the mechanism of action of these various nephrotoxicants. For example, although puromycin is thought to specifically promote injury of the podocytes in the glomerulus, the changes in gene expression after chronic exposure of this compound suggested a pattern similar to the known proximal tubular nephrotoxicants cisplatin and gentamicin; this prediction was confirmed histologically. We conclude that renal gene expression profiling coupled with analysis of classical end points affords promising opportunities to reveal potential new mechanistic markers of renal toxicity.
authors.affiliation: National Institute of Environmental Health Sciences, National Institutes of Health/DHHS, Research Triangle Park, North Carolina, USA.
authors.forename: Rupesh P
authors.initials: RP
authors.lastname: Amin
authors.forename: Alison E
authors.initials: AE
authors.lastname: Vickers
authors.forename: Frank
authors.initials: F
authors.lastname: Sistare
authors.forename: Karol L
authors.initials: KL
authors.lastname: Thompson
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Roman
authors.forename: Michael
authors.initials: M
authors.lastname: Lawton
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kramer
authors.forename: Hisham K
authors.initials: HK
authors.lastname: Hamadeh
authors.forename: Jennifer
authors.initials: J
authors.lastname: Collins
authors.forename: Sherry
authors.initials: S
authors.lastname: Grissom
authors.forename: Lee
authors.initials: L
authors.lastname: Bennett
authors.forename: C Jeffrey
authors.initials: CJ
authors.lastname: Tucker
authors.forename: Stacie
authors.initials: S
authors.lastname: Wild
authors.forename: Clive
authors.initials: C
authors.lastname: Kind
authors.forename: Victor
authors.initials: V
authors.lastname: Oreffo
authors.forename: John W
authors.initials: JW
authors.lastname: Davis
authors.forename: Sandra
authors.initials: S
authors.lastname: Curtiss
authors.forename: Jorge M
authors.initials: JM
authors.lastname: Naciff
authors.forename: Michael
authors.initials: M
authors.lastname: Cunningham
authors.forename: Raymond
authors.initials: R
authors.lastname: Tennant
authors.forename: James
authors.initials: J
authors.lastname: Stevens
authors.forename: Bruce
authors.initials: B
authors.lastname: Car
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Bertram
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Afshari
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity; D000970:Antineoplastic Agents / Q000633:toxicity; D002945:Cisplatin / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D023381:Endpoint Determination; D020869:Gene Expression Profiling; D005819:Genetic Markers; D005839:Gentamicins / Q000633:toxicity; D007668:Kidney / Q000187:drug effects* / Q000473:pathology*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011691:Puromycin / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000900:Anti-Bacterial Agents; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D005819:Genetic Markers; D005839:Gentamicins; D011691:Puromycin; D002945:Cisplatin