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.