Role of protein kinase C in cisplatin nephrotoxicity

Background: Cisplatin is widely used in cancer treatment. The major disadvantage of this antitumor agent is its nephrotoxicity. The mechanism of cisplatin-induced nephrotoxicity has not been clarified. Recent evidence suggests protein kinase C (PKC)-related signal transduction pathways may modulate cisplatin-induced cytotoxicity. Methods: The effect of cisplatin administration on PKC expression in the kidney and the effect of a PKC inhibitor on cisplatin-induced renal impairment were investigated in rats. Results: A single intraperitoneal injection of 8 mg/kg cisplatin induced remarkable damage in the proximal tubules located in the outer medulla, which was associated with impaired renal function, within 48 h. An immunoblotting study revealed marked expression of a-PKC in membrane fractions of medullary tubules prepared from cisplatin-treated rats. In addition, pretreatment with the PKC inhibitor (H-7) protected kidneys from cisplatin-induced damage. Conclusions: These findings suggest that the nephrotoxic effects of cisplatin may, in part, be related to PKC activation in the renal tubules.