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Nephritogenic ochratoxin A interferes with hormonal signalling in immortalized human kidney epithelial cells

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Abstract

The ubiquitous nephritogenic and carcinogenic fungal metabolite ochratoxin A (OTA) affects function and growth of renal epithelial cells. We studied the possible contribution of changes in cellular Ca2+ homeostasis to the effects of nanomolar concentrations of OTA on immortalized human kidney epithelial (IHKE-1) cells. The effects of OTA on cellular calcium homeostasis ([Ca2+]i), cell proliferation and viability and its interaction with angiotensin II (Ang II) and epidermal growth factor (EGF) were investigated. OTA potentiated EGF- and Ang II-induced cell proliferation Ca2+ dependently at OTA concentrations of 0.1 or 1 nmol/l. A decrease in cell viability could be observed only after 24 h exposure, with threshold concentrations greater than 10 nmol/l. This reduction of cell viability was independent of Ca2+. Within seconds, OTA evoked reversible and concentration-dependent [Ca2+]i oscillations with a threshold concentration of ≤0.1 nmol/l. These oscillations were abolished by removal of extracellular Ca2+, by the Ca2+-channel blocker SKF 96365 and by inhibition of phospholipase C. OTA also stimulated thapsigargin-sensitive Ca2+-ATPase activity and increased the filling state of thapsigargin-sensitive Ca2+-stores. Exposure to OTA concentration dependently increased cellular adenosine 3',5'-cyclic monophosphate (cAMP) content. In addition, OTA-induced changes of [Ca2+]i were reduced significantly by the protein kinase A inhibitor H-89. Finally, 0.1 or 1 nmol/l OTA potentiated the effects of Ang II and EGF on cellular Ca2+ homeostasis. We conclude that OTA may impair cellular Ca2+ and cAMP homeostasis already at low nanomolar concentrations, resulting in concentration-dependent [Ca2+]i oscillations. OTA interferes also with hormonal Ca2+ signalling, thereby leading to altered cell proliferation. The reduction of cell viability at higher OTA concentrations seems not to depend on Ca2+.

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Received after revision: 20 September 1999

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Benesic, A., Mildenberger, S. & Gekle, M. Nephritogenic ochratoxin A interferes with hormonal signalling in immortalized human kidney epithelial cells. Pflügers Arch – Eur J Physiol 439, 278–287 (2000). https://doi.org/10.1007/s004249900172

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  • DOI: https://doi.org/10.1007/s004249900172

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