title: COX2 activity promotes organic osmolyte accumulation and adaptation of renal medullary interstitial cells to hypertonic stress.
abstract: The mechanism by which COX2 inhibition decreases renal cell survival is poorly understood. In the present study we examined the effect of COX2 activity on organic osmolyte accumulation in renal medulla and in cultured mouse renal medullary interstitial cells (MMICs) and its role in facilitating cell survival. Hypertonicity increased accumulation of the organic osmolytes inositol, sorbitol, and betaine in cultured mouse medullary interstitial cells. Pretreatment of MMICs with a COX2-specific inhibitor (SC58236, 10 micromol/liter) dramatically reduced osmolyte accumulation (by 79 +/- 9, 57 +/- 12, and 96 +/- 10% for inositol, sorbitol, and betaine respectively, p < 0.05). Similarly, 24 h of dehydration increased inner medullary inositol, sorbitol, and betaine concentrations in vivo by 85 +/- 10, 197 +/- 28, and 190 +/- 24 pmol/microg of protein, respectively, but this increase was also blunted (by 100 +/- 5, 66 +/- 15, and 81 +/- 9% for inositol, sorbitol, and betaine, respectively, p < 0.05) by pretreatment with an oral COX2 inhibitor. Dehydrated COX2-/- mice also exhibited an impressive defect in sorbitol accumulation (88 +/- 9% less than wild type, p < 0.05) after dehydration. COX2 inhibition (COX2 inhibitor-treated or COX2-/- MMICs) dramatically reduced the expression of organic osmolyte uptake mechanisms including betaine (BGT1) and sodium-myo-inositol transporter and aldose reductase mRNA expression under hypertonic conditions. Importantly, preincubation of COX2 inhibitor-treated MMICs with organic osmolytes restored their ability to survive hypertonic stress. In conclusion, osmolyte accumulation in the kidney inner medulla is dependent on COX2 activity, and providing exogenous osmolytes reverses COX2-induced cell death. These findings may have implications for the pathogenesis of analgesic nephropathy.
authors.affiliation: Renal Pathology Division, Department of Pathology, Vanderbilt School of Medicine, Nashville, Tennessee 37232, USA. gilbert.moeckel@vanderbilt.edu
authors.forename: Gilbert W
authors.initials: GW
authors.lastname: Moeckel
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Agnes B
authors.initials: AB
authors.lastname: Fogo
authors.forename: Chuan-Ming
authors.initials: CM
authors.lastname: Hao
authors.forename: Ambra
authors.initials: A
authors.lastname: Pozzi
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Breyer
mesh_terms: D000222:Adaptation, Physiological; D000449:Aldehyde Reductase / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001622:Betaine / Q000378:metabolism* / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation; D003681:Dehydration / Q000201:enzymology / Q000378:metabolism; D015870:Gene Expression; D006360:Heat-Shock Proteins / Q000235:genetics; D006982:Hypertonic Solutions; D020287:In Situ Nick-End Labeling; D007294:Inositol / Q000378:metabolism* / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D007679:Kidney Medulla / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011451:Prostaglandin-Endoperoxide Synthases / Q000172:deficiency / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D013012:Sorbitol / Q000378:metabolism* / Q000494:pharmacology; D027981:Symporters / Q000235:genetics; D014316:Tritium
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D006360:Heat-Shock Proteins; D006982:Hypertonic Solutions; D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D027981:Symporters; D014316:Tritium; C073884:SLC5A3 protein, human; D001622:Betaine; D007294:Inositol; D013012:Sorbitol; D000449:Aldehyde Reductase; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases