Ochratoxin A induces JNK activation and apoptosis in MDCK-C7 cells at nanomolar concentrations

Citation
M. Gekle et al., Ochratoxin A induces JNK activation and apoptosis in MDCK-C7 cells at nanomolar concentrations, J PHARM EXP, 293(3), 2000, pp. 837-844
Citations number
38
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
ISSN journal
0022-3565 → ACNP
Volume
293
Issue
3
Year of publication
2000
Pages
837 - 844
Database
ISI
SICI code
0022-3565(200006)293:3<837:OAIJAA>2.0.ZU;2-2
Abstract
Ochratoxin A (OTA) is a ubiquitous fungal metabolite with nephritogenic, ca rcinogenic, and teratogenic action. Epidemiological studies indicate that O TA may be involved in the pathogenesis of different forms of human nephropa thies. Previously we have shown that OTA activates extracellular signal-reg ulated kinases 1 and 2, members of the mitogen-activated protein kinases (M APK) family, in the C7-clone but not in the C11-clone of renal epithelial M adin-Darby canine kidney (MDCK) cells. Here we show that nanomolar concentr ations of OTA lead to activation of a second member of the MAPK family, nam ely, c-jun amino-terminal-kinase (JNK) in MDCK-C7 cells but virtually not i n MDCK-C11 cells, as determined by kinase assay and Western blot. Furthermo re, OTA potentiated the effect of tumor necrosis factor-alpha on JNK activa tion. In parallel to its effects on JNK, nanomolar OTA induced apoptosis in MDCK-C7 cells but not in MDCK-C11 cells, as determined by DNA fragmentatio n, DNA ladder formation, and caspase activation. In addition, OTA potentiat ed the proapoptotic action of tumor necrosis factor-alpha. Our data provide additional evidence that OTA interacts in a cell type-specific way with di stinct members of the MAPK family at concentrations where no acute toxic ef fect can be observed. Induction of apoptosis via the JNK pathway can explai n some of the OTA-induced changes in renal function as well as part of its teratogenic action.