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 alpha-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.
Ikeda
S
S
Department of Urology, Tohoku University School of Medicine, Sendai, Japan.
Fukuzaki
A
A
Kaneto
H
H
Ishidoya
S
S
Orikasa
S
S
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D007274:Injections, Intraperitoneal; D007674:Kidney Diseases / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D007677:Kidney Function Tests; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; D002945:Cisplatin