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.

Hintergrund: Eine Form der Blutwäsche bei chronischem Nierenversagen ist die Peritonealdialyse (PD). Dabei kommt es zur Loslösung von Mesothelzellen (MZ), die das Peritoneum auskleiden, und in Folge zu Schäden der Peritonealmembran. Da ein Großteil der Zellen in der Peritonealhöhle phagozytierende Monozyten/Makrophagen (MΦ) sind, ist es Ziel dieser Studie zu untersuchen, ob losgelöste MZ von diesen Zellen aufgenommen werden.

Hintergrund: Peritonealdialyseflüssigkeiten (PDF) schädigen Mesothelzellen und führen dadurch zur Fibrosierung und zum zunehmenden Verlust der Ultrafiltrationskapazität des Peritoneums. Hitzeschockproteine (HSPs) können gegen diese Schädigung schützen. Unlängst wurde bei längeren PDF Behandlungszeiten eine abfallende HSP Produktion beobachtet. Ziel dieser Studie ist die Untersuchung dieser inadäquaten Stressantwort auf dem Niveau der Regulationsmechanismen.

Although ETV6/RUNX1 (E/R)-positive ALL is generally associated with excellent treatment response, up to 20% of cases suffer a relapse. To gain insight into relapse mechanisms we analyzed genome-wide copy number aberrations in 18 matched diagnosis and relapse leukemias. Strikingly, we identified recurrent deletions of genes implicated in glucocorticoid (GC) mediated apoptosis affecting NR3C1 and BMF encoding the GC receptor and the Bcl2 modifying factor, respectively. BMF deletions were present in about 17% of children already at initial diagnosis and conserved at relapse, but were significantly less frequent (<3%) in cases without a relapse. By contrast, NR3C1 deletions prevailed at relapse (28% vs. 6% at diagnosis). Functional studies showed that loss of BMF or NR3C1 leads to haploinsufficiency and GC-resistance in E/R-positive leukemic cell lines. Importantly, preliminary analyses suggest that these deletions are clinically relevant. These data need, however, to be confirmed in a larger number of unselected cases.