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Vol. 293, Issue 3, 837-844, June 2000

Ochratoxin A Induces JNK Activation and Apoptosis in MDCK-C7 Cells at Nanomolar Concentrations1

Michael Gekle, Gerald Schwerdt, Ruth Freudinger, Sigrid Mildenberger, Doris Wilflingseder, Verena Pollack, Martina Dander and Herbert Schramek

Physiologisches Institut, Würzburg, Germany (M.G., G.S., R.F., S.M.); and Department of Physiology, University of Innsbruck, Innsbruck, Austria (D.W., V.P., M.D., H.S.)

Ochratoxin A (OTA) is a ubiquitous fungal metabolite with nephritogenic, carcinogenic, and teratogenic action. Epidemiological studies indicate that OTA may be involved in the pathogenesis of different forms of human nephropathies. Previously we have shown that OTA activates extracellular signal-regulated kinases 1 and 2, members of the mitogen-activated protein kinases (MAPK) family, in the C7-clone but not in the C11-clone of renal epithelial Madin-Darby canine kidney (MDCK) cells. Here we show that nanomolar concentrations of OTA lead to activation of a second member of the MAPK family, namely, c-jun amino-terminal-kinase (JNK) in MDCK-C7 cells but virtually not in MDCK-C11 cells, as determined by kinase assay and Western blot. Furthermore, OTA potentiated the effect of tumor necrosis factor-alpha on JNK activation. 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 fragmentation, DNA ladder formation, and caspase activation. In addition, OTA potentiated the proapoptotic action of tumor necrosis factor-alpha . Our data provide additional evidence that OTA interacts in a cell type-specific way with distinct members of the MAPK family at concentrations where no acute toxic effect can be observed. Induction of apoptosis via the JNK pathway can explain some of the OTA-induced changes in renal function as well as part of its teratogenic action.

1 This work was supported by the Deutsche Forschungsgemeinschaft (Ge 905/3-4 to M.G.) and the Austrian Science Foundation (Grant P13295-MED to H.S.).

0022-3565/00/2933-0837$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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