title: Hypertonic stress activates glycogen synthase kinase 3beta-mediated apoptosis of renal medullary interstitial cells, suppressing an NFkappaB-driven cyclooxygenase-2-dependent survival pathway.
abstract: The survival of renal medullary interstitial cells (RMICs) requires their adaptation to rapid shifts in ambient tonicity normally occurring in the renal medulla. Previous studies determined that cyclooxygenase-2 (COX 2) activation is critical for this adaptation. The present studies find that these adaptive mechanisms are dampened by the simultaneous activation of an apoptotic pathway linked to a glycogen synthase kinase 3beta (GSK 3beta). Inhibition of GSK 3 by LiCl or specific small molecule GSK inhibitors increased RMIC survival following hypertonic stress, and transduction of RMICs with a constitutively active GSK 3beta (AdGSK 3betaA9) significantly increased apoptosis, consistent with a proapoptotic role of GSK 3beta. Following GSK 3beta inhibition, increased survival was accompanied by increased COX 2 expression and COX 2 reporter activity. In contrast, GSK 3beta overexpression reduced COX 2 reporter activity. Importantly, enhanced RMIC survival produced by GSK 3beta inhibition was completely dependent on COX 2 because it was abolished by a COX 2-specific inhibitor, SC58236. The signaling pathway by which GSK 3beta suppresses COX 2 expression was then explored. GSK 3beta inhibition increased both NFkappaB and beta-catenin activity associated with decreased IkappaB and increased beta-catenin levels. The increase in COX 2 following GSK 3beta inhibition was entirely blocked by NFkappaB inhibition using mutant IkappaB adenovirus. However, adenoviral overexpression of beta-catenin did not increase COX 2 levels. These findings suggest that GSK 3beta negatively regulates COX 2 expression and that GSK 3beta inhibitors protect RMICs from hypertonic stress via induction of NFkappaB-COX 2-dependent pathway.
authors: Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors: Reena
authors: R
authors: Rao
authors: Chuan-Ming
authors: CM
authors: Hao
authors: Matthew D
authors: MD
authors: Breyer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006982:Hypertonic Solutions; D007527:Isoenzymes / Q000378:metabolism*; D007679:Kidney Medulla / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D018021:Lithium Chloride / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D009997:Osmotic Pressure; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011817:Rabbits; D015398:Signal Transduction; D014161:Transduction, Genetic
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D006982:Hypertonic Solutions; D007527:Isoenzymes; D016328:NF-kappa B; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride