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2014 ; 25
(12
): 2778-88
Nephropedia Template TP
gab.com Text
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English Wikipedia
Dynamic O-linked N-acetylglucosamine modification of proteins affects stress
responses and survival of mesothelial cells exposed to peritoneal dialysis
fluids
#MMPMID24854264
Herzog R
; Bender TO
; Vychytil A
; Bialas K
; Aufricht C
; Kratochwill K
J Am Soc Nephrol
2014[Dec]; 25
(12
): 2778-88
PMID24854264
show ga
The ability of cells to respond and survive stressful conditions is determined,
in part, by the attachment of O-linked N-acetylglucosamine (O-GlcNAc) to proteins
(O-GlcNAcylation), a post-translational modification dependent on glucose and
glutamine. This study investigates the role of dynamic O-GlcNAcylation of
mesothelial cell proteins in cell survival during exposure to glucose-based
peritoneal dialysis fluid (PDF). Immortalized human mesothelial cells and primary
mesothelial cells, cultured from human omentum or clinical effluent of PD
patients, were assessed for O-GlcNAcylation under normal conditions or after
exposure to PDF. The dynamic status of O-GlcNAcylation and effects on cellular
survival were investigated by chemical modulation with 6-diazo-5-oxo-L-norleucine
(DON) to decrease or O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino N-phenyl
carbamate (PUGNAc) to increase O-GlcNAc levels. Viability was decreased by
reducing O-GlcNAc levels by DON, which also led to suppressed expression of the
cytoprotective heat shock protein 72. In contrast, increasing O-GlcNAc levels by
PUGNAc or alanyl-glutamine led to significantly improved cell survival paralleled
by higher heat shock protein 72 levels during PDF treatment. Addition of
alanyl-glutamine increased O-GlcNAcylation and partly counteracted its inhibition
by DON, also leading to improved cell survival. Immunofluorescent analysis of
clinical samples showed that the O-GlcNAc signal primarily originates from
mesothelial cells. In conclusion, this study identified O-GlcNAcylation in
mesothelial cells as a potentially important molecular mechanism after exposure
to PDF. Modulating O-GlcNAc levels by clinically feasible interventions might
evolve as a novel therapeutic target for the preservation of peritoneal membrane
integrity in PD.