title: GSK-3β inhibition protects mesothelial cells during experimental peritoneal dialysis through upregulation of the heat shock response.
abstract: Non-physiological components of peritoneal dialysis fluids (PDF) lead to the injury of peritoneal mesothelial cells resulting in the failure of peritoneal dialysis (PD) potentially via inadequate induction of the protective heat shock response (HSR). Glycogen synthase kinase-3β (GSK-3β) is a negative regulator of cell survival partly by suppression of the HSR and is influenced by stress stimuli also present in conventional PDF. The effects of PDF on GSK-3β activation and the impact of GSK-3β inhibition with lithium (LiCl) were investigated on cell survival with special regard to HSR, in particular to heat shock transcription factor 1 (HSF-1) activation and Hsp72 production in an in vitro model of PD using MeT-5A and primary mesothelial cells. Incubation of cells with the PDF Dianeal® (glucose-based, low pH, high glucose degradation products (GDP)) and Extraneal® (icodextrin-based, low pH, low GDP) caused activation of GSK-3β compared to the other tested PDF, i.e. Balance®, Physioneal® (normal pH, glucose-based, low GDP) and Nutrineal® (moderately acidic, amino acid-based). Inhibition of GSK-3β with LiCl in Dianeal® and Extraneal®-treated cells dose-dependently decreased cell damage and death rate and was paralleled by higher HSF-1 activation and Hsp72 expression. GSK-3β is activated by low pH GDP containing PDF with and without glucose as osmotic agent, indicating that GSK-3β is involved in mesothelial cell signalling in response to experimental PD. Inhibition of GSK-3β with LiCl ameliorated cell injury and improved HSR upon PDF exposure. Thus, GSK-3β inhibitors likely have therapeutic potential as cytoprotective additive for decreasing PDF toxicity.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Rusai
authors.forename: R
authors.initials: R
authors.lastname: Herzog
authors.forename: L
authors.initials: L
authors.lastname: Kuster
authors.forename: K
authors.initials: K
authors.lastname: Kratochwill
authors.forename: C
authors.initials: C
authors.lastname: Aufricht
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D015314:Dialysis Solutions / Q000633:toxicity*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005936:Glucans / Q000633:toxicity*; D005947:Glucose / Q000633:toxicity*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006153:Guanosine Diphosphate / Q000494:pharmacology; D050884:HSP72 Heat-Shock Proteins / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response / Q000187:drug effects*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D000077607:Icodextrin; D018021:Lithium Chloride / Q000494:pharmacology; D010530:Peritoneal Dialysis; D010537:Peritoneum / Q000166:cytology; D010766:Phosphorylation; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D004268:DNA-Binding Proteins; D015314:Dialysis Solutions; D005936:Glucans; C000619706:HSF1 protein, human; D050884:HSP72 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D014157:Transcription Factors; D006153:Guanosine Diphosphate; D000077607:Icodextrin; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride; D005947:Glucose