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.
Highlights
Peritoneal dialysis (PD) is an established treatment for endstage renal disease.[1]
We further examined the peritoneal mesothelial cells from patient treated with 2.5% dextrose or 7.5% of icodextrin PD solution by immunofluorescence staining of salt-inducible kinase 2 (SIK2) and LC3B
We demonstrated that the proteasome activity was inhibited and autophagy was promoted in peritoneal mesothelial cells exposed to PD solution both in vitro and in vivo
Summary
Peritoneal dialysis (PD) is an established treatment for endstage renal disease.[1]. Successful treatment depends on the preserved functional integrity of the peritoneal membrane. Peritoneal mesothelial cells have important roles in mediating leukocyte trafficking, maintenance of peritoneal homeostasis, antigen presentation, inflammation and tissue repair.[2,3,4,5,6] Approximately 20–30% of patients treated with PD gradually lose peritoneal membrane function, which compromises the efficiency of dialysis and leads to treatment failure.[7] Partial or total disappearance of mesothelial cells, loss of peritoneal membrane integrity and peritoneal fibrosis develop in a majority of these patients.[8,9,10] prolonging and maintaining mesothelial cell survival is critical for long-term preservation of the peritoneum as a dialyzing organ.[11].
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