title: Proteasome or immunoproteasome inhibitors cause apoptosis in human renal tubular epithelial cells under normoxic and hypoxic conditions.
abstract: OBJECTIVE
  Ischemic acute kidney injury is characterized by apoptosis of tubular epithelial cells. Proteasome plays a key role in cellular processes such as proliferation, apoptosis and inflammation. The results of animal studies about the effect of proteasome inhibitors on the course of ischemic acute kidney injury are controversial.
  
  
  METHODS
  Primary human renal tubular epithelial cells were cultured with or without the hypoxia mimetic CoCl2 and with or without the proteasome inhibitor CEP-18770 and/or the immunoproteasome inhibitor ONX-0914. The level of the proteasome subunit β5, the immunoproteasome subunits LMP7 and LMP2, the function of these proteolytic machines, HIF-1α and its transcriptional target lactate dehydrogenase-A, p53 and its transcriptional targets TP53-inducible glycolysis and apoptosis regulator and p21, and finally of activated cleaved caspase-3 were assessed by means of western blotting.
  
  
  RESULTS
  CoCl2 decreased the expression of β5, LMP7 and LMP2, as well as the activity of proteasome and immunoproteasome. It increased HIF-1α and its function, along with p53 and its function and induced apoptosis. CEP-18770 and ONX-0914 induced the above alterations toward the same directions as CoCl2 does. In CoCl2-treated cells, pretreatment with CEP-18770 and/or ONX-0914 potentiates the changes induced by CoCl2 alone.
  
  
  CONCLUSIONS
  CoCl2, CEP-18770 and ONX-0914 induce apoptosis in human renal tubular epithelial cells. Importantly, proteasome or immunoproteasome inhibitors are rather toxic than beneficial in human renal tubular epithelial cells treated with the hypoxia mimetic CoCl2.
authors.affiliation: Department of Nephrology, Medical School, University of Thessaly, Neo Ktirio, Mezourlo Hill, 41110, Larissa, Greece. teleftheriadis@yahoo.com.
authors.forename: Theodoros
authors.identifier: http://orcid.org/0000-0001-9302-1633
authors.initials: T
authors.lastname: Eleftheriadis
authors.affiliation: Department of Nephrology, Medical School, University of Thessaly, Neo Ktirio, Mezourlo Hill, 41110, Larissa, Greece.
authors.forename: Georgios
authors.initials: G
authors.lastname: Pissas
authors.affiliation: Department of Nephrology, Medical School, University of Thessaly, Neo Ktirio, Mezourlo Hill, 41110, Larissa, Greece.
authors.forename: Georgia
authors.initials: G
authors.lastname: Antoniadi
authors.affiliation: Department of Nephrology, Medical School, University of Thessaly, Neo Ktirio, Mezourlo Hill, 41110, Larissa, Greece.
authors.forename: Vassilios
authors.initials: V
authors.lastname: Liakopoulos
authors.affiliation: Department of Nephrology, Medical School, University of Thessaly, Neo Ktirio, Mezourlo Hill, 41110, Larissa, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Stefanidis
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology*; D018929:Cell Culture Techniques; D015687:Cell Hypoxia; D004847:Epithelial Cells / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D007684:Kidney Tubules / Q000187:drug effects* / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D013912:Threonine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D001897:Boronic Acids; D009842:Oligopeptides; C542291:PR-957; D061988:Proteasome Inhibitors; D013912:Threonine; C527966:delanzomib
keywords: Acute kidney injury; Apoptosis; HIF; Immunoproteasome; Ischemia; Proteasome; p53