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.
Highlights
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
Prostanoids Produced in Cultured RMICs—To identify potential prostanoid(s) responsible for the survival-promoting effect of COX2 in RMICs, the profile of prostanoids synthesized by these cells was examined by gas chromatography/mass spectrometry
Summary
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. Overexpression of PPAR␦ using an adenovirus drove DRE activity and 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 PPAR␦. 1 The abbreviations used are: RMIC, renal medullary interstitial cell; NSAID, non-steroidal anti-inflammatory drug; PG, prostaglandin; IP receptor, prostacyclin receptor; PPAR, peroxisome proliferator-activated receptor; RT, reverse transcription; Ad, adenovirus; GFP, green fluorescent protein; DRE, delta response element; TK, thymidine kinase; cPGI2, carbaprostacyclin. COX2-selective inhibitors cause RMICs to die when exposed to otherwise non-lethal hypertonic stress [4] These results may account for the finding that RMICs are an early site of injury caused by COX-inhibiting analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) [5, 6]. The goal of the present studies was to identify the COX2-derived products and their downstream targets promoting cell survival following hypertonic stress
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