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

The ubiquitous nephritogenic and carcinogenic fungal metabolite ochratoxin A (OTA) affects function and growth of renal epithelial cells. We studied t he possible contribution of changes in cellular Ca2+ homeostasis to the eff ects of nanomolar concentrations of OTA on immortalized human kidney epithe lial (IHKE-1) cells. The effects of OTA on cellular calcium homeostasis ([C a2+](i)), cell proliferation and viability and its interaction with angiote nsin II (Ang II) and epidermal growth factor (EGF) were investigated. OTA p otentiated EGF- and Ang II-induced cell proliferation Ca2+ dependently at O TA 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 t han 10 nmol/l. This reduction of cell viability was independent of Ca2+ Wit hin seconds, OTA evoked reversible and concentration-dependent [Ca2+](i) os cillations with a threshold concentration of less than or equal to 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. OT A also stimulated thapsigargin-sensitive Ca2+-ATPase activity and increased the filling state of thapsigargin-sensitive Ca2+-stores. Exposure to OTA c oncentration dependently increased cellular adenosine 3',5'-cyclic monophos phate (cAMP) content. In addition, OTA-induced changes of [Ca2+](i) were re duced significantly by the protein kinase A inhibitor H-89. Finally, 0.1 or I nmol/l OTA potentiated the effects of Ang II and EGF on cellular Ca2+ ho meostasis. We conclude that OTA may impair cellular Ca2+ and cAMP homeostas is already at low nanomolar concentrations, resulting in concentration-depe ndent [Ca2+](i) oscillations. OTA interferes also with hormonal Ca2+ signal ling, thereby leading to altered cell proliferation. The reduction of cell viability at higher OTA concentrations seems not to depend on Ca2+.