Stimulation of the renal endoplasmic reticulum calcium pump: A possible biomarker for platinate toxicity

Abstract

Antitumor platinum compounds such as cisplatin are frequently nephrotoxic. The mechanism of nephrotoxicity has not been determined. It has been proposed that some toxicants may act by interfering with the mechanisms that control cellular Ca 2+ homeostasis. An important factor in the regulation of cytosolic Ca 2+ is the endoplasmic reticulum (ER) calcium pump. The activity of this pump was determined by measuring ATP-dependent microsomal sequestration of 45Ca. Administration of nephrotoxic doses of platinum compounds to rats was associated with an increase in renal ER calcium pump activity. This was the earliest response observed after cisplatin treatment (it occurred within 4 hr) and preceded increases in blood urea nitrogen and serum creatinine by at least 1 day. The dose-response curve for the increase in renal ER calcium pump activity was similar to the increase in the number and size of smooth ER aggregates observed in the S 3 segment of the proximal tubule 24 hr following cisplatin administration. Only minor morphological changes were observed at this time. There was a significant increase in calcium content of kidneys of rats 24 hr after treatment with a dose of cisplatin that caused a maximal increase in ER calcium pump activity. This indicates that a disruption of normal calcium homeostasis may occur before histological evidence of nephrotoxicity. Platinates that were not toxic to the kidney did not elevate renal ER calcium pump activity. It is suggested that the activity of the ER calcium pump may be a useful biomarker for cellular toxicity and may be a factor in the mechanism of toxicity.