Alanyl–glutamine dipeptide restores the cytoprotective stress proteome of mesothelial cells exposed to peritoneal dialysis fluids

Kratochwill, Klaus; Böehm, Michael; Herzog, Rebecca; Lichtenauer, Anton Michael; Salzer, Elisabeth; Lechner, Michael; Kuster, Lilian; Bergmeister, Konstantin D.; Rizzi, Andreas; Mayer, Bernd; Aufricht, Christoph

doi:10.1093/ndt/gfr459

Cited by 37 publications

(70 citation statements)

References 36 publications

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“…As a first step, we therefore investigated the activation and expression of GSK-3β in mesothelial cells in an in vitro PD model, established recently by our group in order to study the cellular stress responses upon exposure to PDF (Kratochwill et al 2012). Following exposure to different PDF, cells demonstrated selective GSK-3β activation upon Dianeal® (high glucose, high GDPs, low pH) and upon Extraneal® (icodextrin-based, low GDPs, low pH) exposure.…”

Section: Discussionmentioning

confidence: 99%

“…Human peritoneal mesothelial cells (HPMCs) were isolated from peritoneal effluent of consenting uraemic patients as described previously (Kratochwill et al 2012). Patients were clinically stable and for more than 3 months free of peritonitis at the time of effluent collection.…”

Section: Methodsmentioning

confidence: 99%

“…PDF incubation of HPMCs was performed as described previously and published by our study group (Kratochwill et al 2012). Briefly, confluent cultures on 12-well plates were exposed for 6 h to the studied PDF diluted to 1:1 with normal cell culture medium or kept in parallel in control medium, before testing for LDH release and Western blot analysis of Hsp72 and/or p-GSK-3β were performed.…”

Section: Methodsmentioning

confidence: 99%

“…Several studies of our group demonstrated that HSPmediated cytoprotection has indeed a significant impact on mesothelial cell survival in experimental PD (Bender et al 2010(Bender et al , 2011. Cells in which HSP expression was decreased or remained unchanged after PDF exposure had a significantly higher susceptibility to PDF toxicity (Kratochwill et al 2012). On the other hand, pharmacological (Boehm et al 2010;Kratochwill et al 2012) or plasmid-mediated (Bidmon et al 2004) upregulation of the HSR or specific HSP protected cells from the toxic features of PDF.…”

Section: Introductionmentioning

confidence: 92%

“…Cells in which HSP expression was decreased or remained unchanged after PDF exposure had a significantly higher susceptibility to PDF toxicity (Kratochwill et al 2012). On the other hand, pharmacological (Boehm et al 2010;Kratochwill et al 2012) or plasmid-mediated (Bidmon et al 2004) upregulation of the HSR or specific HSP protected cells from the toxic features of PDF.…”

Section: Introductionmentioning

confidence: 98%

See 4 more Smart Citations

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

Rusai

Kuster

Kratochwill

et al. 2013

Cell Stress and Chaperones

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 98%

See 3 more Smart Citations

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

Rusai

Kuster

Kratochwill

et al. 2013

Cell Stress and Chaperones

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Blockade of thrombospondin‐1 ameliorates high glucose‐induced peritoneal fibrosis through downregulation of TGF‐β1/Smad3 signaling pathway

Jiang

Zhang

Shao

et al. 2019

Journal Cellular Physiology

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Background: Transforming growth factor-β1 (TGF-β1) is a profibrotic cytokine which induces mesothelial cell mesothelial-to-mesenchymal transition (MMT) and peritoneal fibrosis in patients receiving treatment of peritoneal dialysis. Because thrombospondin-1 (TSP-1) is able to activate latent TGF-β1 in vivo, we investigated whether blockade of TSP-1 could modulate mesothelial cell MMT and ameliorate peritoneal fibrosis.Methods: Human pleural mesothelial cells (Met-5A cells) were treated with TSP-1 and addition of TGF-β1 neutralizing antibody to assess the effect of TSP-1 on MMT.Furthermore, TSP-1 blocking peptide Leu-Ser-Lys-Leu (LSKL) was applied to Met-5A cells treated with 4.25% D-glucose to determine its function in high glucose-induced MMT. Consequently, a uremic dialysate injection rat model was set up to confirm the results in vivo. Results: Exposure of Met-5A cells to TSP-1 increased TGF-β1 secretion, expression and bioactivity, triggered Smad3 phosphorylation, upregulated the expression of mesenchymal molecules including fibronectin, collagen type III, α-smooth muscle actin, Snail, and decreased calretinin expression. The effect was partially attenuated by TGF-β1 neutralizing antibody. TSP-1 expression in Met-5A cells was increased by 4.25% D-glucose, followed by increased secretion and bioactivity of TGF-β1, the onset of Smad3 phosphorylation and induction of MMT. LSKL significantly attenuated high glucose-mediated mesothelial cell MMT and ameliorated peritoneal fibrosis in uremic rats receiving dextrose dialysate injection. Conclusions: Taken together, these data demonstrated that TSP-1 contributes to mesothelial cell MMT by activating TGF-β1/Smad3 signaling pathway and blockade of TSP-1 attenuates high glucose-mediated mesothelial cell MMT and peritoneal fibrosis. K E Y W O R D S mesothelial-to-mesenchymal transition, peritoneal dialysis, peritoneal fibrosis, thrombospondin-1, transforming growth factor-β1 *Na Jiang and Zhen Zhang contributed equally to this work.

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Is there such a thing as biocompatible peritoneal dialysis fluid?

Schmitt

Aufricht

2016

Pediatr Nephrol

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Introduction of the so-called biocompatible peritoneal dialysis (PD) fluids was based on a large body of experimental evidence and various clinical trials suggesting important clinical benefits. Of these, until now, only preservation of residual renal function—likely due to lower glucose degradation product load and, in case of icodextrin, improved fluid and blood pressure control—have consistently been proven, whereas the impact on important clinical endpoints such as infectious complications, preservation of PD membrane transport function, and patient outcome, are still debated. In view of the high morbidity and mortality rates of PD patients, novel approaches are warranted and comprise the search for alternative osmotic agents and enrichment of PD fluids with specific pharmacologic agents, such as alanyl-glutamine, potentially counteracting local but also systemic sequelae of uremia and PD.

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Alanyl–glutamine dipeptide restores the cytoprotective stress proteome of mesothelial cells exposed to peritoneal dialysis fluids

Cited by 37 publications

References 36 publications

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

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

Blockade of thrombospondin‐1 ameliorates high glucose‐induced peritoneal fibrosis through downregulation of TGF‐β1/Smad3 signaling pathway

Is there such a thing as biocompatible peritoneal dialysis fluid?

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