title: Peroxisome proliferator-activated receptor delta activation promotes cell survival following hypertonic stress.
abstract: COX2-selective non-steroidal anti-inflammatory drugs (NSAIDs) cause selective apoptosis of renal medullary interstitial cells (RMIC) in vivo and reduce their ability to tolerate hypertonic stress in vitro. To determine the mechanism by which COX2 activity promotes RMIC viability, we examined the capacity of COX2-derived prostanoids to promote RMIC survival. Although RMICs synthesize prostaglandin E2 (PGE2) PGI2 > PGF2a > TxA2, only PGI2 enhanced RMIC viability following hypertonic stress. RMICs do not express the prostacyclin receptor, but they do express the prostacyclin responsive nuclear transcription factor peroxisome proliferator-activated receptor delta (PPARdelta). Hypertonic stress increased PGI2 synthesis 330% above base line and also activated a PPARdelta specific reporter (delta response element (DRE)) by 90% above base line. Conversely DRE activity was only inhibited by the COX2-selective inhibitor SC236 but not by a COX1-selective NSAID (SC560). Overexpression of PPARdelta using an adenovirus not only drove DRE activity but also prevented RMIC death due to COX2 inhibition. These studies are consistent with a model whereby hypertonicity activates COX2-derived prostaglandin production, which promotes RMIC viability through PPARdelta. Inhibition of PPARdelta activity may contribute to the renal papillary necrosis associated with analgesic and/or NSAID use.
authors.affiliation: Division of Nephrology and Department of Pharmacology, Vanderbilt University and Department of Veterans Affairs Hospital, Nashville, Tennessee 37232, USA. chuanming.hao@mcmail.vanderbilt.edu
authors.forename: Chuan-Ming
authors.initials: CM
authors.lastname: Hao
authors.forename: Reyadh
authors.initials: R
authors.lastname: Redha
authors.forename: Jason
authors.initials: J
authors.lastname: Morrow
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Breyer
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D017930:Genes, Reporter; D015151:Immunoblotting; D007527:Isoenzymes / Q000378:metabolism; D009336:Necrosis; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism; D011485:Protein Binding; D011720:Pyrazoles / Q000494:pharmacology; D011817:Rabbits; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*; D000096926:Benzenesulfonamides
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000242:Cyclic AMP; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone; D004791:Enzyme Inhibitors; D011464:Epoprostenol; D007527:Isoenzymes; D010975:Platelet Aggregation Inhibitors; D011451:Prostaglandin-Endoperoxide Synthases; D011453:Prostaglandins; D011720:Pyrazoles; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; D014157:Transcription Factors; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C026678:carboprostacyclin