Prostaglandin E2 stimulates expression of osmoprotective genes in MDCK cells and promotes survival under hypertonic conditions.
The cells of the renal medulla produce large amounts of prostaglandin E2 (PGE2) via cyclooxygenases (COX)-1 and -2. PGE2 is well known to play a critical role in salt and water balance and maintenance of medullary blood flow. Since renal medullary PGE2 production increases in antidiuresis, and since COX inhibition is associated with damage to the renal medulla during water deprivation, PGE2 may promote the adaptation of renal papillary cells to high interstitial solute concentrations. To address this question, MDCK cells were exposed to a gradual tonicity increase in the presence or absence of 20 microM PGE2 prior to analysis of (i) cell survival, (ii) expression of osmoprotective genes (AR, BGT1, SMIT, HSP70 and COX-2), (iii) subcellular TonEBP/NFAT5 abundance, (iv) TonEBP/NFAT5 transcriptional activity and (v) aldose reductase promoter activity. Cell survival and apoptotic indices after raising the medium tonicity improved markedly in the presence of PGE2. PGE2 significantly increased tonicity-mediated up-regulation of AR, SMIT and HSP70 mRNAs. However, neither nuclear abundance nor TonEBP/NFAT5-driven reporter activity were elevated by PGE2, but aldose reductase promoter activity was significantly increased by PGE2. Interestingly, tonicity-induced COX-2 expression and activity was also stimulated by PGE2, suggesting the existence of a positive feedback loop. These results demonstrate that the major medullary prostanoid, PGE2, stimulates the expression of osmoprotective genes and favours the adaptation of medullary cells to increasing interstitial tonicities, an effect that is not explained directly by the presence of TonEs in the promoter region of the respective target genes. These findings may be relevant in the pathophysiology of medullary damage associated with analgesic drugs.
Neuhofer
Wolfgang
W
Department of Physiology, University of Munich, Germany. wolfgang.neuhofer@med.uni-muenchen.de
Steinert
Daniela
D
Fraek
Maria-Luisa
ML
Beck
Franz-X
FX
D000449:Aldehyde Reductase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D015232:Dinoprostone / Q000502:physiology*; D004285:Dogs; D050485:GABA Plasma Membrane Transport Proteins; D005786:Gene Expression Regulation; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D007679:Kidney Medulla / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D012462:Saline Solution, Hypertonic / Q000009:adverse effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002352:Carrier Proteins; D050485:GABA Plasma Membrane Transport Proteins; D018840:HSP70 Heat-Shock Proteins; D050778:NFATC Transcription Factors; D012462:Saline Solution, Hypertonic; C072207:betaine plasma membrane transport proteins; D000449:Aldehyde Reductase; D007770:L-Lactate Dehydrogenase; D011451:Prostaglandin-Endoperoxide Synthases; D053148:Caspase 3; D015232:Dinoprostone