title: Enhancement of protein kinase C activity and chemiluminescence intensity in mitochondria isolated from the kidney cortex of rats treated with cephaloridine.
abstract: The development of nephrotoxicity induced by cephaloridine (CER) has been reported to be due to reactive oxygen species (ROS). Protein kinase C (PKC) has been suggested to modulate the generation of ROS. We investigated the possible participation of ROS generation assessed by chemiluminescence (CL) and PKC activity in rat kidney cortical mitochondria in the development of CER-induced nephrotoxicity. We first evaluated the magnitude of the nephrotoxic damage caused by CER in rats. The plasma parameters and ultrastructural morphology changes were increased markedly 24hr after the treatment of rats with CER. We demonstrated that the treatment of rats with CER clearly evoked not only enhancement of Cypridina luciferin analog (CLA)-dependent CL intensity, but also the activation of PKC in mitochondria isolated from the kidney cortex of rats 1.5 and 3.5 hr after injection of the drug. These changes were detected in advance of those observed in plasma and by electron microscopy. The increase in CLA-dependent CL intensity detected in the kidney cortical mitochondria 1.5 and 3.5 hr after injection of CER was inhibited completely by the addition of superoxide dismutase, suggesting the generation of superoxide anion in these mitochondria during the early stages of CER-induced nephrotoxicity. These results suggest that the activation of PKC and the enhancement of superoxide anion generation in kidney cortical mitochondria precede the increases in plasma parameters and the electron micrographic changes indicative of renal dysfunction in rats treated with CER. Additionally, they suggest a possible relationship between PKC activation in mitochondria and free radical-induced CER nephrotoxicity in rats.
authors.affiliation: Division of Pharmacology, Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, 569-1094, Osaka, Japan. kohda@gly.oups.ac.jp
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kohda
authors.forename: Munekazu
authors.initials: M
authors.lastname: Gemba
mesh_terms: D000818:Animals; D002509:Cephaloridine / Q000633:toxicity*; D002511:Cephalosporins / Q000633:toxicity*; D007672:Kidney Cortex / Q000166:cytology / Q000187:drug effects*; D008163:Luminescent Measurements; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D011719:Pyrazines / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D051437:Renal Insufficiency / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology
chemical_list: D002511:Cephalosporins; D011719:Pyrazines; D017382:Reactive Oxygen Species; C048193:2-methyl-6-phenyl-3,7-dihydroimidazo(1,2-a)pyrazin-3-one; D011493:Protein Kinase C; D002509:Cephaloridine