Pharmacologic Targets and Peritoneal Membrane Remodeling

Farhat, Karima; Stavenuiter, Andrea W.D.; Beelen, R.H.J.; Wee, Piet M. ter

doi:10.3747/pdi.2011.00332

Cited by 13 publications

(13 citation statements)

References 91 publications

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“…Many therapeutic interventions have been investigated with the aim of preventing some of the major pathologic processes, such as the fibroblast activation, inflammation, and angiogenesis, involved in peritoneal fibrosis. 46,47 Our studies indicate that inhibition of EGFR with gefitinib can suppress all those processes and attenuate both the generation and progression of peritoneal fibrosis. These results were consistent with the results of previous studies designed to examine the renoprotective effects of EGFR inhibition in renal fibrosis, and they suggest that the inhibition of EGFR may help protect against peritoneal fibrosis.…”

Section: Discussionmentioning

confidence: 83%

Inhibition of EGF Receptor Blocks the Development and Progression of Peritoneal Fibrosis

Wang

Liu

Xiong

et al. 2015

JASN

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Inhibitors of EGF receptor (EGFR) have antifibrotic effects in several organs, but the effect of these inhibitors on the development of peritoneal fibrosis is unknown. Here, we explored the therapeutic effect of gefitinib, a specific inhibitor of EGFR, on the development and progression of peritoneal fibrosis in a rat model. Daily intraperitoneal injections of chlorhexidine gluconate induced peritoneal fibrosis, indicated by thickening of the submesothelial area with an accumulation of collagen fibrils and activation of myofibroblasts, accompanied by time-dependent phosphorylation of EGFR. Administration of gefitinib immediately after injury prevented the onset of peritoneal fibrosis and delayed administration after the onset of peritoneal fibrosis halted fibrosis progression. Gefitinib treatment abrogated the increased phosphorylation of EGFR, Smad3, signal transducer and activator of transcription 3, and NF-kB during peritoneal fibrosis; it also inhibited the accompanying overproduction of TGF-b1 and proinflammatory cytokines and the infiltration of macrophages to the injured peritoneum. Moreover, gefitinib significantly reduced the peritoneal increase of CD31-positive blood vessels and vascular EGF-positive cells after injury. Finally, gefitinib also attenuated high glucoseinduced peritoneal fibrosis in rats and abrogated TGF-b1-induced phosphorylation of Smad3 and the epithelial-to-mesenchymal transition of cultured human peritoneal mesothelial cells. These results demonstrate that EGFR contributes to peritoneal fibrosis, inflammation, and angiogenesis, suggesting that EGFR inhibitors may have therapeutic potential in attenuating peritoneal fibrosis.

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Section: Discussionmentioning

confidence: 83%

Inhibition of EGF Receptor Blocks the Development and Progression of Peritoneal Fibrosis

Wang

Liu

Xiong

et al. 2015

JASN

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“…3 ). The majority of these compounds (as reviewed in detail in [ 65 ] and in [ 66 ]) have been selected by a hypothesis-driven approach. Several of these compounds are highly specific pharmacologic agents or biologics that counteract specific pathways identified to be relevant in PD-related complications.…”

Section: Future Solutionsmentioning

confidence: 99%

“…For example, peroxisome proliferator-activated receptor (PPAR)-gamma agonists, such as rosiglitazone, have been shown in experimental PD systems to result in improved membrane integrity and to reduce inflammation. Addition of bone morphogenic protein (BMP)-7 mitigates mechanisms such as chronic inflammation and EMT (reviewed in detail in [ 65 ], [ 66 ]). More recently, use of antagomir has proven to effectively counteract peritoneal fibrosis in a rodent model of PD [ 67 ].…”

Section: Future Solutionsmentioning

confidence: 99%

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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“…These changes to the peritoneal membrane ultimately contribute to ultrafiltration failure, resulting in technique failure and discontinuation of PD therapy [6]. Consequently, the most important challenge currently faced in PD is the prevention of PF and the long-term preservation of peritoneal membrane structure and function [7].…”

Section: Introductionmentioning

confidence: 99%

Effects of Astragaloside IV Against the TGF-β1-Induced Epithelial-to-Mesenchymal Transition in Peritoneal Mesothelial Cells by Promoting Smad 7 Expression

Zhang

et al. 2015

Cell Physiol Biochem

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Background/Aims: To investigate the effect of Astragaloside IV (AS-IV) on the regulation of the TGF-β1/Smad signaling pathway in peritoneal mesothelial cells with an epithelial-to-mesenchymal transition (EMT). Methods: EMT of human peritoneal mesothelial cells (HMrSV5) was induced using 2 ng/ml TGF-β1. Cells were randomly divided into a vehicle group, a vehicle group with AS-IV, a TGF-β1 treated group, and a TGF-β1 treated group receiving varied doses of AS-IV or NAC. Real-time quantitative PCR and western blot were used to detect the expression of genes and proteins associated with the TGF-β1/Smad signaling pathway and EMT. DCFH-DA was used to detect the generation of ROS in HMrSV5 cells, and a transwell migration assay was used to verify the capacity of AS-IV to inhibit EMT in HMrSV5 cells. Lentiviruses were used as carriers for the overexpression or knockdown of the Smad7 gene. Results: Expression levels of E-cadherin (epithelial marker) was decreased and vimentin, α-SMA (EMT markers) and collagen I (extracellular matrix protein) phospho-Smad2/3, Snail1 and Snail2 was increased significantly in the TGF-β1-treated HMrSV5 cells. AS-IV was associated with downregulated expression of vimentin and phospho-Smad2/3 in a dose-dependent manner, while the expression of Smad7 increased. Silenced or forced expression of Smad7 verified its role in the inhibitory effect of AS-IV on TGF-β1-induced EMT in HMrSV5 cells. Conclusion: AS-IV effectively promotes the upregulation of Smad7 in the TGF-β1/Smad signaling pathway during the EMT of HMrSV5 cells, indicating its potential therapeutic effect for the control of PF.

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Pharmacologic Targets and Peritoneal Membrane Remodeling

Cited by 13 publications

References 91 publications

Inhibition of EGF Receptor Blocks the Development and Progression of Peritoneal Fibrosis

Inhibition of EGF Receptor Blocks the Development and Progression of Peritoneal Fibrosis

Is there such a thing as biocompatible peritoneal dialysis fluid?

Effects of Astragaloside IV Against the TGF-β1-Induced Epithelial-to-Mesenchymal Transition in Peritoneal Mesothelial Cells by Promoting Smad 7 Expression

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