Alterations in calcium homeostasis as a possible cause of ochratoxin A nephrotoxicity.

Disruption of calcium homeostasis, leading to a sustained increase in cytosolic calcium level, has been associated with cytotoxicity in response to a variety of agents in different cell types. We have observed that a single high dose or multiple lower doses of ochratoxin A administered to rats resulted in an increase in renal endoplasmic reticulum calcium pump activity. The increase was very rapid, being evident within 10 min of ochratoxin A administration and remained elevated for at least 6 h thereafter. Ochratoxin A also decreased renal mitochondrial state-3 respiration and calcium uptake. The latter may lead to an increase in cytosolic calcium level, and the increase in microsomal calcium uptake activity may be an attempt to restore calcium homeostasis. Repeated moderate doses of ochratoxin A led to an eventual decrease in microsomal calcium pump activity, and this could lead to even higher cytosolic calcium levels. Changes in the rate of microsomal calcium uptake correlated with changes in the steady-state levels of the phosphorylated Mg2+/Ca(2+)-ATPase intermediate, indicating that this enzyme is responsible for the calcium pump activity.