Identification of genes involved in gentamicin-induced nephrotoxicity in rats--a toxicogenomic investigation.
For the application of microarray technology as an additional endpoint in toxicological studies, there is a need to understand associations between pathological processes and gene expression alterations. In the current study, we investigated gentamicin as a nephrotoxic model compound. Gene expression changes of the kidney in response to a dose of 80 mg/kg gentamicin were analyzed by using DNA microarray technology and alterations in gene expression were associated with results from conventional histopathological investigations and with the described pathomechanisms of gentamicin. Under the conditions of our experiment, the mRNA level of 211 genes were found to be deregulated by gentamicin. The gentamicin-induced affection of proximal convoluted tubules was associated with a strong up-regulation of mRNAs encoding for proteins which are used as nephrotoxicity markers in urine and plasma such as Kim-1, Osteopontin and TIMP1. Candidate marker genes for nephrotoxicity such as GATM were deregulated. Gentamicin-induced lysosomal phospholipidosis was indicated by deregulation of lysosomal located gene products such as ATP6V1D, a subunit of the lysosomal H+ transporting ATPase. Effects on glucose transport and metabolism were indicated by the down-regulation on SGLT-2 and glucose-6-phosphatase. Renal cell apoptosis was indicated by up-regulated genes as TP53 and BAX. The role of oxidative stress in gentamicin toxicity was reflected by deregulation of transferrin receptor and heme oxygenase. The results of the study show the potential of microarray technology to study a complex mechanism of toxicity in a single study.
Ozaki
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Department of Molecular & Cellular Biology, Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd. 6-7-5, Minatojima-Minamimachi Chuo-ku, Kobe, Hyogo 650-0047, Japan.
Matheis
K A
KA
Gamber
M
M
Feidl
T
T
Nolte
T
T
Kalkuhl
A
A
Deschl
U
U
D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D005839:Gentamicins / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar
D000900:Anti-Bacterial Agents; D005839:Gentamicins; D012333:RNA, Messenger