GSK-3β inhibition protects mesothelial cells during experimental peritoneal dialysis through upregulation of the heat shock response

Rusai, Krisztina; Kuster, Lilian; Kratochwill, Klaus; Aufricht, Christoph

doi:10.1007/s12192-013-0410-6

Cited by 10 publications

(10 citation statements)

References 51 publications

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“…The activation of HSF-1, the key transcription factor of Hsp72, is a multistep process involving multiple regulators that might be independently regulated by factors prevalent in PDF. 48,49 O-GlcNAc-mediated regulation of HSF-1 is also supported by the recent work by Kazemi et al, 23 which reported a link between Hsp72, HSF-1, glycogen synthase kinase 3b, and O-GlcNAcylation. Recently, we have shown that the addition of glutamine to PDF protects mesothelial cells in in vitro and in vivo models of PD by enhancing CSRs after PDF exposure.…”

Section: Discussionmentioning

confidence: 52%

“…Although ex vivo exposure to diluted PDF still represents an artificial system, this model likely reflects the conditions prevalent during an intraperitoneal PD dwell and has previously been shown to be suitable for assessing the balance of mesothelial cell injury and repair processes. 46,49 In conclusion, this study identified O-GlcNAcylation in mesothelial cells as a potentially important PTM after exposure to PDF. Dynamic changes of O-GlcNAc levels on PDF exposure were shown in immortalized mesothelial cells and primary cultures of HPMCs obtained from patients on PD.…”

Section: Discussionmentioning

confidence: 58%

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Dynamic O-Linked N-Acetylglucosamine Modification of Proteins Affects Stress Responses and Survival of Mesothelial Cells Exposed to Peritoneal Dialysis Fluids

Bender

Vychytil

Bialas

et al. 2014

Journal of the American Society of Nephrology

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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-Dglucopyranosylidene)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.

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 58%

Dynamic O-Linked N-Acetylglucosamine Modification of Proteins Affects Stress Responses and Survival of Mesothelial Cells Exposed to Peritoneal Dialysis Fluids

Bender

Vychytil

Bialas

et al. 2014

Journal of the American Society of Nephrology

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“…Interestingly, the 6BIO-mediated effect on chaperone ( e.g ., hsp70 gene) upregulation was not dependent on CncC/Nrf-2 and in fact CncC/Nrf-2 knockdown further increased hsp70 upregulation. In support, Gsk-3 exerted a repressive action on the transcriptional activation of Hsf-1 ( 10 , 61 ), and Gsk-3 β inhibition protected mesothelial cells during experimental peritoneal dialysis through upregulation of the heat shock response ( 44 ). Notably, Gsk-3 also enhanced the transactivation activity of Foxo in both mammalian ( 22 ) and in Drosophila S2 ( 32 ) cells; and it also positively regulated autophagic flux in hippocampal neural stem cells ( 19 ) and in fibroblasts ( 63 ).…”

Section: Discussionmentioning

confidence: 87%

The Indirubin Derivative 6-Bromoindirubin-3′-Oxime Activates Proteostatic Modules, Reprograms Cellular Bioenergetic Pathways, and Exerts Antiaging Effects

Tsakiri

Gaboriaud‐Kolar

Iliaki

et al. 2017

Antioxidants & Redox Signaling

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Aims: Organismal aging can be delayed by mutations that either activate stress responses or reduce the nutrient-sensing pathway signaling; thus, by using Drosophila melanogaster as an in vivo experimental screening platform, we searched for compounds that modulate these pathways.Results: We noted that oral administration of the glycogen synthase kinase 3 (Gsk-3) inhibitor 6-bromoindirubin-3′-oxime (6BIO) in Drosophila flies extended healthy life span. 6BIO is not metabolized in fly tissues, modulated bioenergetic pathways, decreased lipid and glucose tissue load, activated antioxidant and proteostatic modules, and enhanced resistance to stressors. Mechanistically, we found that the effects on the stress-responsive pathways were largely dependent on the activity of the transcription factor nuclear factor erythroid 2-related factor (Nrf-2). Genetic inhibition of Gsk-3 largely phenocopied the 6BIO-mediated effects, while high levels of Gsk-3 expression and/or kinase activity suppressed proteostatic modules and reduced flies' longevity; these effects were partially rescued by 6BIO. Also, 6BIO was found to partially reduce the 3-phosphoinositide-dependent protein kinase-1 (Pdpk1) activity, a major effector of the insulin/insulin-like growth factor-1 cell signaling pathways.Innovation: 6BIO exerts the unique property of increasing stress tolerance and in parallel partially suppressing the nutrient-sensing pathway signaling.Conclusion: Our findings suggest that the 6BIO scaffold can be used for the development of novel antiaging compounds. Antioxid. Redox Signal. 27, 1027–1047.

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“…Genetic deletion of GSK-3b in cardiac fibroblasts promotes fibrogenesis and excessive scarring in the ischemic heart [39]. Independent researchers have also reported on the activation of GSK-3b in mesothelial cells exposed to glucose-based dialysate, whereas inhibition of GSK-3b activation using specific GSK-3b inhibitors was associated with mesothelial cell cytoprotection [40]. It has been shown that activation of AKT/PI3K and p38 MAPK signaling inactivates GSK-3b and promotes myocardial protection [41].…”

Section: Discussionmentioning

confidence: 99%

Anti-fibrotic effect of decorin in peritoneal dialysis and PD-associated peritonitis

et al. 2020

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Background: Progressive peritoneal fibrosis is a common complication in patients on long-term peritoneal dialysis (PD). PD-associated peritonitis is a major exacerbating factor. We investigated the anti-fibrotic properties of decorin secreted by peritoneal mesothelial cells. Methods: Dialysate decorin level in stable PD patients and those with peritonitis was measured. In vitro experiments were conducted to investigate the effect of decorin in fibrotic response in human peritoneal mesothelial cells (HPMC). Findings: Increasing PD duration was associated with a progressive decrease of dialysate decorin and CA125 levels. Dialysate decorin level correlated with CA125 level. Peritonitis episodes were associated with a massive drop of dialysate decorin, which persisted for over three months despite clinical recovery. Dialysate decorin level correlated with that of TGF-b1, but was inversely related to IL-1b and IL-8. TGF-b1, IL-1b, IL-6, IL-8, or TNF-a reduced decorin secretion in HPMC, but induced fibronectin expression. The effects were mediated in part through increased p38 MAPK and AKT/PI3K phosphorylation. Decorin abrogated the induction of fibronectin expression in mesothelial cells by PD fluids or pro-fibrotic cytokines, through decreased TGF-bRI, p38 MAPK and AKT/PI3K phosphorylation and increased glycogen synthase kinase-3b phosphorylation. Decorin gene-silencing resulted in increased fibronectin expression under these conditions. Interpretation: Our data demonstrate anti-fibrotic actions of decorin in HPMC, when these cells are subjected to the pro-fibrotic effect of peritoneal dialysate and pro-fibrotic cytokines in PD, especially during peritonitis.

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GSK-3β inhibition protects mesothelial cells during experimental peritoneal dialysis through upregulation of the heat shock response

Cited by 10 publications

References 51 publications

Dynamic O-Linked N-Acetylglucosamine Modification of Proteins Affects Stress Responses and Survival of Mesothelial Cells Exposed to Peritoneal Dialysis Fluids

Dynamic O-Linked N-Acetylglucosamine Modification of Proteins Affects Stress Responses and Survival of Mesothelial Cells Exposed to Peritoneal Dialysis Fluids

The Indirubin Derivative 6-Bromoindirubin-3′-Oxime Activates Proteostatic Modules, Reprograms Cellular Bioenergetic Pathways, and Exerts Antiaging Effects

Anti-fibrotic effect of decorin in peritoneal dialysis and PD-associated peritonitis

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