Time- and concentration-dependent biphasic effect of ochratoxin A on growth of proximal tubular cells in primary culture.

Ochratoxin A (OTA) leads to trophic and functional changes in the proximal tubule of the kidney. We investigated the effects of micromolar and nanomolar concentrations of OTA on cell growth, cell viability and transepithelial transport in rat proximal tubular cells in primary culture. Micromolar concentrations of OTA exerted a hypotrophic and hypoplastic effect after 24 hr, but a hypertrophic and hypoplastic effect after 72 hr. These effects could be abolished in a concentration-dependent manner by the addition of albumin to the medium. In parallel, micromolar concentrations reduced cell viability, monolayer integrity and abolished the formation of transepithelial gradients of Na+ and K+. Nanomolar concentrations of OTA had neither hypotrophic nor hypertrophic effects, but stimulated DNA synthesis and cell division, leading to hyperplasia. At the same time, nanomolar concentrations did not reduce cell viability or the formation of electrolyte gradients. Lowering extracellular pH to 6.8 abolished the effect of nanomolar concentrations of OTA on DNA synthesis and cell number as well as the effect of micromolar concentrations on cellular protein. Cellular alkalinization (pH 7.7) also stimulated proliferation, but did not act additively with nanomolar concentrations of OTA. From these results, we conclude that OTA exerts a time-dependent biphasic effect on cellular protein content and a concentration-dependent biphasic effect on DNA synthesis. The stimulatory effect is independent of its toxic action. Modulation of both effects by extracellular pH suggests that cellular pH-homeostasis may be involved in the action of OTA.