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.

Autophagy in Chronic Kidney Diseases

“…The activation of Beclin 1-dependent autophagy results in decreases of the viability of peritoneal mesothelium cells and finally PD failure [105]. Another study, however, suggests that the PD solution promotes autophagosome formation and decreases cells death to maintain the PD function [106]. Therefore, future studies are required to understand the exact relationship of dialysis and autophagy regulation.…”

Autophagy Activation in Peripheral Blood Mononuclear Cells of Peritoneal Dialysis Patients

“…In patients undergoing PD treatment, the mesothelial cells exposed to PD solution showed a significant activation of the autophagy and inhibition of proteasome activity to maintain the viability of mesothelial cells during renal replacement therapy. 39 Contrarily, another study reported that autophagy promoted epithelial to mesenchymal transition, fibrosis, and apoptosis in human peritoneal mesothelial cells. 40 …”

Sirtuin 3-mediated pyruvate dehydrogenase activity determines brown adipocytes phenotype under high-salt conditions

“…Sik2 is highly enriched in interscapular BAT. Phosphorylation of SIK2 at Thr175/Thr163 is the hallmark of its kinase activation 38,39 . However, the role of HS in lipid metabolism and fat deposition is debated.…”