title: Integrated transcriptomic and proteomic evaluation of gentamicin nephrotoxicity in rats.
abstract: Gentamicin is an aminoglycoside antibiotic, which induces renal tubular necrosis in rats. In the context of the European InnoMed PredTox project, transcriptomic and proteomic studies were performed to provide new insights into the molecular mechanisms of gentamicin-induced nephrotoxicity. Male Wistar rats were treated with 25 and 75 mg/kg/day subcutaneously for 1, 3 and 14 days. Histopathology observations showed mild tubular degeneration/necrosis and regeneration and moderate mononuclear cell infiltrate after long-term treatment. Transcriptomic data indicated a strong treatment-related gene expression modulation in kidney and blood cells at the high dose after 14 days of treatment, with the regulation of 463 and 3241 genes, respectively. Of note, the induction of NF-kappa B pathway via the p38 MAPK cascade in the kidney, together with the activation of T-cell receptor signaling in blood cells were suggestive of inflammatory processes in relation with the recruitment of mononuclear cells in the kidney. Proteomic results showed a regulation of 163 proteins in kidney at the high dose after 14 days of treatment. These protein modulations were suggestive of a mitochondrial dysfunction with impairment of cellular energy production, induction of oxidative stress, an effect on protein biosynthesis and on cellular assembly and organization. Proteomic results also provided clues for potential nephrotoxicity biomarkers such as AGAT and PRBP4 which were strongly modulated in the kidney. Transcriptomic and proteomic data turned out to be complementary and their integration gave a more comprehensive insight into the putative mode of nephrotoxicity of gentamicin which was in accordance with histopathological findings.
authors: sanofi-aventis R&D, Disposition Safety and Animal Research, Vitry-sur-Seine, France. emmanuelle.com@univ-rennes1.fr
authors: Emmanuelle
authors: E
authors: Com
authors: Eric
authors: E
authors: Boitier
authors: Jean-Pierre
authors: JP
authors: Marchandeau
authors: Arnd
authors: A
authors: Brandenburg
authors: Susanne
authors: S
authors: Schroeder
authors: Dana
authors: D
authors: Hoffmann
authors: Angela
authors: A
authors: Mally
authors: Jean-Charles
authors: JC
authors: Gautier
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D015415:Biomarkers; D020869:Gene Expression Profiling; D005839:Gentamicins / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D040901:Proteomics; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000900:Anti-Bacterial Agents; D015415:Biomarkers; D005839:Gentamicins