Genomic reprograming analysis of the Mesothelial to Mesenchymal Transition identifies biomarkers in peritoneal dialysis patients

Ruiz-Carpio, Vicente; Sandoval, Pilar; Aguilera, Abelardo; Albar-Vizcaíno, Patricia; Perez-Lozano, M L; González-Mateo, Guadalupe; Acuña-Ruíz, Adrián; García-Cantalejo, Jesús; Botías, Pedro; Bajo, María Auxiliadora; Selgas, Rafael; Sánchez-Tomero, José Antonio; Passlick–Deetjen, Jutta; Piecha, Dorothea; Büchel, Janine; Steppan, Sonja; López–Cabrera, Manuel

doi:10.1038/srep44941

Cited by 38 publications

(46 citation statements)

References 60 publications

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“…Additional fibrosis gene expression analysis in Dianeal/low-exposed HPMCthe cell type known to contribute to peritoneal fibrosis by acquiring a fibroblastic phenotype following epithelial-tomesenchymal transdifferentiation (EMT)showed a 3-fold increase in the expression of VGEFA (main isoform of VGEF) and a reduction in E-cadherin (Supplementary Figure S3), both effects indicating EMT. 12,13…”

Section: Pro-inflammatory and Pro-fibrotic Effects Of Different Pd Somentioning

confidence: 99%

Targeting Toll-like receptors with soluble Toll-like receptor 2 prevents peritoneal dialysis solution–induced fibrosis

Raby

González-Mateo

Williams

et al. 2018

Kidney International

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Peritoneal membrane failure due to fibrosis limits the use of peritoneal dialysis (PD). Peritoneal fibrosis may potentially be induced by sterile inflammation caused by ongoing cellular stress due to prolonged exposure to PD solutions (PDS). Effective therapies to prevent this process remain to be developed. Toll-like receptors (TLRs) mediate sterile inflammation by recognizing damage-associated molecular patterns (DAMPs) released by cellular stress. We evaluated the involvement of TLRs and DAMPs in PDS-induced fibrosis models and the therapeutic potential of TLR-DAMP targeting for preventing fibrosis. A range of PDS elicited pro-inflammatory and fibrotic responses from PD patient peritoneal leukocytes, mesothelial cells and mouse peritoneal leukocytes. TLR2/4 blockade of human peritoneal cells or TLR2/4 knockouts inhibited these effects. PDS did not induce rapid ERK phosphorylation or IκB-α degradation, suggesting that they do not contain components capable of direct TLR activation. However, PDS increased the release of Hsp70 and hyaluronan, both TLR2/4 DAMP ligands, by human and mouse peritoneal cells, and their blockade decreased PDS-driven inflammation. Soluble TLR2, a TLR inhibitor, reduced PDS-induced pro-inflammatory and fibrotic cytokine release ex vivo. Daily catheter infusion of PDS in mice caused peritoneal fibrosis, but co-administration of soluble TLR2 prevented fibrosis, suppressed pro-fibrotic gene expression and pro-inflammatory cytokine production, reduced leukocyte/neutrophil recruitment, recovered Treg cell levels and increased the Treg:Th17 ratio. Thus, TLR2/4, Hsp70 and hyaluronan showed major roles in PDS-induced peritoneal inflammation and fibrosis. The study demonstrates the therapeutic potential of a TLR-DAMP targeting strategy to prevent PDS-induced fibrosis.

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Section: Pro-inflammatory and Pro-fibrotic Effects Of Different Pd Somentioning

confidence: 99%

Targeting Toll-like receptors with soluble Toll-like receptor 2 prevents peritoneal dialysis solution–induced fibrosis

Raby

González-Mateo

Williams

et al. 2018

Kidney International

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“…mRNA array data processing and normalization was performed using the Babelomics 5 software (Computational Genomics Department, Prince Felipe Research Center, Valencia, Spain). 29,32 Fluorescence raw signal from each probe was corrected with the subtraction of local background and normalized with the loess method (within arrays) or the quantile method (between arrays). Fold change for a gene was determined as a quotient between normalized data from samples under study.…”

Section: Discussionmentioning

confidence: 99%

“…mRNA array results presented in this article can be found in Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/ geo; accession number GSE92455). 29…”

Section: Discussionmentioning

confidence: 99%

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miR-21 Promotes Fibrogenesis in Peritoneal Dialysis

Lopez-Anton

Lambie

López–Cabrera

et al. 2017

The American Journal of Pathology

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Peritoneal dialysis (PD) is a life-saving form of renal replacement therapy for those with end-stage kidney disease. Mesothelial cells (MCs) line the peritoneal cavity and help define peritoneal response to treatment-associated injury, a major reason for treatment failure. miRNAs are important regulators, but their roles in peritoneal fibrosis are largely unknown. In this study, miR-21 was one of the most abundant miRNAs in primary MCs, and was up-regulated by the profibrotic cytokine transforming growth factor-β1 and in PD effluent-derived MCs exhibiting mesenchymal phenotypic change. Increased miR-21 was found in peritoneal membrane biopsy specimens from PD patients compared to healthy controls (PD biocompatible, 5.86×, P = 0.0001; PD conventional, 7.09×, P < 0.0001, n = 11 per group). In PD effluent from a cohort of 230 patients, miR-21 was higher in those receiving the therapy long-term compared to new starters (n = 230, miR-21 3.26×, P = 0.001) and associated with icodextrin use (R = 0.52; 95% CI, 0.20-0.84), peritonitis count (R = 0.16; 95% CI, 0.03-0.29), and dialysate cytokines. miR-21 down-regulated programmed cell death 4 and programmed cell death 4 protein was decreased in peritoneal membrane biopsy specimens from PD patients compared to healthy controls. New miR-21 targets were identified that may be important during PD fibrogenesis. These data identify miR-21 as an important effector of fibrosis in the peritoneal membrane, and a promising biomarker in the dialysis effluent for membrane change in patients receiving PD.

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“…The structure of the peritoneal membrane (PM) is composed of a single layer of highly specialized mesothelial cells that lines a compact zone, which includes few fibroblasts, mast cells, macrophages and blood vessels [1]. This zone also covers an underlying stroma containing extracellular matrix (ECM) and stromal cells [2].…”

Section: Introductionmentioning

confidence: 99%

Exosomes: The New Mediator of Peritoneal Membrane Function

Shi

Sheng³

2018

Kidney Blood Press Res

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Fibrosis and angiogenesis are the most common processes that result in progressive peritoneal tissue remodeling and, eventually, peritoneal membrane dysfunction. The role of exosomes, which contributes to intercellular communication, in these processes has been neglected. Various biomolecules, including DNA, mRNA, proteins, lipids, and particular certain miRNAs, can be transferred by exosomes to local, neighboring and distal cells. Upon stimulation by cytokines or other microenvironment stimuli, donor cells release a mass of exosomes to peritoneal mesothelial cells, further affecting fibrosis and angiogenesis. This important exosomes-mediated intracellular communication is thought to regulate peritoneal membrane function. Understanding the molecular mechanisms of these processes, targeting changes in exosomes and regulating exosomal miRNAs will advance therapeutic methods for protecting peritoneal membrane function.

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Genomic reprograming analysis of the Mesothelial to Mesenchymal Transition identifies biomarkers in peritoneal dialysis patients

Cited by 38 publications

References 60 publications

Targeting Toll-like receptors with soluble Toll-like receptor 2 prevents peritoneal dialysis solution–induced fibrosis

Targeting Toll-like receptors with soluble Toll-like receptor 2 prevents peritoneal dialysis solution–induced fibrosis

miR-21 Promotes Fibrogenesis in Peritoneal Dialysis

Exosomes: The New Mediator of Peritoneal Membrane Function

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