Cyclooxygenase-independent inhibition of H2O2-induced cell death by S-ketoprofen in renal cells.
The stress response of the distal tubule to oxidative attack may be relevant to recovery from acute renal failure. In distal tubular Madin-Darby cells (MDCK), H(2)O(2) induced up-regulation of cyclooxygenases (COX-1 and COX-2), prostaglandin-E(2) production and caspase-independent cell death. Cell death was inhibited by S-ketoprofen, but not by the much weaker COX inhibitor R-ketoprofen. Interestingly, we identified 15-deoxy-Delta(12,14)-prostaglandin-J(2) (15d-PGJ(2)), a peroxisome-proliferator activated receptor-gamma agonist, as a lethal prostaglandin whose effect was reproduced by the PPAR-gamma agonist ciglitazone. Nevertheless, H(2)O(2)-induced cell death was unaffected by other non-steroidal anti-inflammatory drugs (NSAIDs) or all-trans-retinoic acid. Moreover, c-Jun-N-terminal kinase inhibitor SP600125 prevented 15-deoxy-Delta(12,14)-PGJ(2)-induced cell death, but not H(2)O(2)-induced cell death. PPAR-gamma antagonist GW9662 showed no affect on the cell death. These results indicated that protection by S-ketoprofen was COX-independent and PPARgamma independent. Moreover, the IC(50) value of the action of S-ketoprofen for the inhibition of H(2)O(2)-induced MDCK cell death ( approximately equal 140microM) was much higher than the IC(50) value for the inhibition of COX-1 and COX-2 activities ( approximately equal 1microM). Further design of S-ketoprofen derivatives devoid of COX inhibitory activity will give opportunity to protect the kidney against oxidative attack while avoiding unwanted effects of NSAID.
Reyes-Martin
Patricia
P
Physiology, University of Alcala, Alcala de Henares, Madrid, Spain.
Alique
Matilde
M
Parra
Trinidad
T
Hornedo
Jaime Perez de
JP
Lucio-Cazana
Javier
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D007660:Ketoprofen / Q000737:chemistry / Q000494:pharmacology*; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018374:LLC-PK1 Cells; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016877:Oxidants / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D020011:Protective Agents / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism; D013552:Swine
C477819:15-deoxyprostaglandin J2; D016861:Cyclooxygenase Inhibitors; D016877:Oxidants; D047495:PPAR gamma; D020011:Protective Agents; D007660:Ketoprofen; D006861:Hydrogen Peroxide; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D015230:Prostaglandin D2