title: Activation of salt-inducible kinase 2 promotes the viability of peritoneal mesothelial cells exposed to stress of peritoneal dialysis.
abstract: Maintaining mesothelial cell viability is critical to long-term successful peritoneal dialysis (PD) treatment. To clarify the viability mechanism of peritoneal mesothelial cells under PD solutions exposure, we examined the mechanisms of cellular response to this stress conditions. Here we report that the proteasome activity is inhibited when treated with PD solutions. Proteasome inhibition-mediated activation of salt-inducible kinase 2 (SIK2), an endoplasmic reticulum-resident protein, is important for mesothelial cell viability. SIK2 is mobilized to promote autophagy and protect the cells from apoptosis under PD solution or MG132 treatment. Immunofluorescence staining showed that SIK2 is colocalized with LC3B in the autophagosomes of mesothelial cells treated with PD solution or derived from patients undergoing PD treatment. SIK2 activation is likely via a two-step mechanism, upstream kinases relieving the autoinhibitory conformation of SIK2 molecule followed by autophosphorylation of Thr175 and activation of kinase activity. These results suggest that activation of SIK2 is required for the cell viability when proteasome activity is inhibited by PD solutions. Maintaining or boosting the activity of SIK2 may promote peritoneal mesothelial cell viability and evolve as a potential therapeutic target for maintaining or restoring peritoneal membrane integrity in PD therapy.
authors.affiliation: Department of Pediatrics, Division of Pediatric Immunology and Nephrology, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Pediatrics, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Institute of Emergency and Critical Care Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: H-H
authors.initials: HH
authors.lastname: Wang
authors.affiliation: Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, Taichung, Taiwan.|Clinical Immunological Center and Division of Pediatric Nephrology, Children's Hospital of China Medical University, Taichung, Taiwan.
authors.forename: C-Y
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Department of Pediatrics, Division of Pediatric Immunology and Nephrology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: S-H
authors.initials: SH
authors.lastname: Su
authors.affiliation: Institute of Molecular Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: C-T
authors.initials: CT
authors.lastname: Chuang
authors.affiliation: Institute of Molecular Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Y-L
authors.initials: YL
authors.lastname: Chang
authors.affiliation: Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: T-Y
authors.initials: TY
authors.lastname: Lee
authors.affiliation: Institute of Molecular Medicine, National Taiwan University, Taipei, Taiwan.|Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: S-C
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.|Graduate Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan.
authors.forename: C-J
authors.initials: CJ
authors.lastname: Chang
mesh_terms: D000071182:Autophagosomes / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D015314:Dialysis Solutions / Q000737:chemistry / Q000494:pharmacology*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009997:Osmotic Pressure; D010530:Peritoneal Dialysis; D010537:Peritoneum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D061251:Primary Cell Culture; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D013314:Stress, Mechanical
chemical_list: D015853:Cysteine Proteinase Inhibitors; D015314:Dialysis Solutions; D007976:Leupeptins; C502070:MAP1LC3B protein, human; D008869:Microtubule-Associated Proteins; C551842:salt-inducible kinase-2, human; D017346:Protein Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde