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Renal epithelial gene expression profile and bismuth-induced resistance against cisplatin nephrotoxicity

Toxicology Laboratory; Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands

Hans J Baelde

Thirza M Broekhuizen-van den Berg

Emile de Heer

Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands

Gijsbert B van der Voet

Toxicology Laboratory, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands g.b.van_der_voet{at}lumc.nl

Anja Slikkerveer

Toxicology Laboratory, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden; Yamanouchi Europe BV, Research Laboratories, Leiderdorp, The Netherlands

Jan A Bruijn

Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands

Frederik A de Wolff

Toxicology Laboratory, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands

Nephrotoxicity is the most important dose-limiting factor in cisplatin based anti-neoplastic treatment. Pretreatment with bismuth salts, used as pharmaceuticals to treat gastric disorders, has been demonstrated to reduce cisplatin-induced renal cell death in clinical settings and during in vivo and in vitro animal experiments. To investigate the genomic basis of this renoprotective effect, we exposed NRK-52E cells, a cell line of rat proximal tubular epithelial origin, to 33 mM Bi³ for 12 hours, which made them resistant to cisplatin-induced apoptosis. Differentially expressed genes in treated and untreated NRK-52E cells were detected by subtraction PCR and microarray techniques. Genes found to be down regulated (0.17 ^/ 0.31-times) were cytochrome c oxidase subunit I, BAR (an apoptosis regulator), heat-shock protein 70-like protein, and three proteins belonging to the translation machinery (ribosomal proteins S7 and L17, and S1, a member of the elongation factor 1-alpha family). The only up-regulated gene was glutathione Stransferase subunit 3A (1.89-times). Guided by the expression levels of these genes, it may be possible to improve renoprotective treatments during anti-neoplastic therapies.

Key Words: bismuth • cisplatin • differential gene expression analysis • nephrotoxicity • platinum • renoprotection

Human & Experimental Toxicology, Vol. 22, No. 10, 535-540 (2003)
DOI: 10.1191/0960327103ht393oa


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