Identification of putative gene based markers of renal toxicity.
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.
Amin
Rupesh P
RP
National Institute of Environmental Health Sciences, National Institutes of Health/DHHS, Research Triangle Park, North Carolina, USA.
Vickers
Alison E
AE
Sistare
Frank
F
Thompson
Karol L
KL
Roman
Richard J
RJ
Lawton
Michael
M
Kramer
Jeffrey
J
Hamadeh
Hisham K
HK
Collins
Jennifer
J
Grissom
Sherry
S
Bennett
Lee
L
Tucker
C Jeffrey
CJ
Wild
Stacie
S
Kind
Clive
C
Oreffo
Victor
V
Davis
John W
JW
Curtiss
Sandra
S
Naciff
Jorge M
JM
Cunningham
Michael
M
Tennant
Raymond
R
Stevens
James
J
Car
Bruce
B
Bertram
Timothy A
TA
Afshari
Cynthia A
CA
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
D000900:Anti-Bacterial Agents; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D005819:Genetic Markers; D005839:Gentamicins; D011691:Puromycin; D002945:Cisplatin