Modulation by cyclic AMP and phorbol myristate acetate of cephaloridine-induced injury in rat renal cortical slices.
Intracellular signaling pathways of cAMP and protein kinase C (PKC) have been suggested to modulate the generation of free radicals. We investigated the effects of cAMP and phorbol myristate acetate (PMA), a PKC activator, on cephaloridine (CER)-induced renal cell injury, which has been reported to be due to the generation of free radicals. Incubation of rat renal cortical slices with CER resulted in increases in lipid peroxidation and lactate dehydrogenase (LDH) release and in decreases in gluconeogenesis and p-aminohippurate (PAH) accumulation in rat renal cortical slices, suggesting free radical-induced injury in slices exposed to CER. A derivative of cAMP ameliorated not only the increase in lipid peroxidation but also the renal cell damage induced by CER. This amelioration by a cAMP derivative of lipid peroxidation and renal cell damage caused by CER was blocked by KT 5720, a protein kinase A (PKA) inhibitor. Lipid peroxidation and the indices of cell injury were increased by PMA. PMA also enhanced CER-induced lipid peroxidation and cell damage in the slices. This enhancement by PMA of CER-induced injury was blocked by H-7, a PKC inhibitor. These results indicated that intracellular signaling pathways of cAMP and PKC modulate free radical-mediated nephrotoxicity induced by CER.
Division of Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki, Japan. kohda@oysun01.oups.ac.jp
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D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000818:Animals; D002227:Carbazoles; D002273:Carcinogens / Q000494:pharmacology; D002509:Cephaloridine / Q000494:pharmacology; D002511:Cephalosporins / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005609:Free Radicals / Q000009:adverse effects / Q000378:metabolism*; D005943:Gluconeogenesis / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007672:Kidney Cortex / Q000293:injuries / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008297:Male; D011493:Protein Kinase C / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D010130:p-Aminohippuric Acid / Q000378:metabolism
D002227:Carbazoles; D002273:Carcinogens; D002511:Cephalosporins; D004791:Enzyme Inhibitors; D005609:Free Radicals; D007211:Indoles; D011758:Pyrroles; C057416:KT 5720; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000242:Cyclic AMP; D007770:L-Lactate Dehydrogenase; D011493:Protein Kinase C; D002509:Cephaloridine; D013755:Tetradecanoylphorbol Acetate; D010130:p-Aminohippuric Acid