CHARACTERIZATION OF AN OCHRATOXIN-A-DEDIFFERENTIATED AND CLONED RENALEPITHELIAL-CELL LINE

Ochratoxin A (OTA) is a ubiquitous fungal metabolite with predominant nephrotoxic action. OTA impairs postproximal renal electrolyte handlin g and increases the incidence of renal adenoma and carcinoma. Furtherm ore, it is supposed to be involved in the pathogenesis of different fo rms of human renal diseases. Previously we have shown that OTA activat es extracellular signal-regulated kinase 1 (ERK1) and ERK2 in the C7 c lone but not in the C11 clone of renal epithelial MDCK cells. Here we show that nanomolar concentrations of OTA lead to stable and irreversi ble phenotypical and genotypical alterations, resulting in sustained d edifferentiation of MDCK-C7 cells but not of MDCK-C11 cells. Dediffere ntiated MDCK-C7 cells (OTA-C7 cells) display a distinct morphology fro m the parent cell line (spindle-shape, pleiomorphic, narrow intercellu lar spaces, increased cell size) and show a reduced proliferation rate and numerical chromosomal aberrations. Functionally, OTA-C7 cells are characterized by a dramatic reduction of transepithelial electrolyte transport and the complete loss of responsiveness to the mineralocorti coid hormone aldosterone. Our data provide further evidence that OTA c an lead to cell dedifferentiation and eventually to transformation of cloned quiescent cells. The changes in phenotype due to this dediffere ntiation could explain some of the OTA-induced changes in renal functi on. (C) 1998 Academic Press.