Inflammation, neoangiogenesis and fibrosis in peritoneal dialysis

Lima, Silvia Maia Alves de; Otoni, Alba; Sabino, Adriano de Paula; Dusse, Luci Maria Sant’Ana; Gomes, Karina Braga; Pinto, Sérgio Wyton Lima; Marinho, Maria Aparecida Silva; Rios, Danyelle Romana Alves

doi:10.1016/j.cca.2013.02.027

Cited by 57 publications

(62 citation statements)

References 77 publications

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“…Inflammation is considered one of the main pathologic processes contributing to peritoneal fibrosis during long-term PD. 4,7 In this study, the expression of multiple proinflammatory factors (TNF-a, MCP-1, IL-b1, and IL-6) increased in the peritoneum of CGinjured rats. Macrophages also accumulated in the submesothelial compact zone after injury.…”

Section: Discussionmentioning

confidence: 55%

“…One of the most important factors is the conventional bioincompatible PD solution, which contains a high concentration of glucose, as well as glucose degradation products and an acidic pH. 3,4 Factors other than those related to the PD fluid, such as uremic toxins and peritonitis, also contribute to this process. 5 All of these factors can damage the peritoneal membrane and subsequently lead to inflammation, fibrosis, and angiogenesis.…”

mentioning

confidence: 99%

“…This process is associated with activation of the NF-kB pathway, 6 overproduction of multiple proinflammatory factors (including TNF-a, IL-b1, IL-6, and monocyte chemoattractant protein-1 [MCP-1]), and infiltration of various inflammatory cells (including macrophages). 4,7 Activated macrophages in the peritoneum release several cytokines and chemokines and produce growth factors that enhance extracellular matrix (ECM) production and exacerbate the fibrotic process. 7 Peritoneal fibrosis and angiogenesis are typical morphologic changes leading to loss of peritoneal functions in patients undergoing PD.…”

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confidence: 99%

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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: 55%

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confidence: 99%

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confidence: 99%

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

Wang

Liu

Xiong

et al. 2015

JASN

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“…Peritoneal fibrosis is characterized by reduction or loss of mesothelial cells, changes in the structure and number of blood vessels, and enlargement of the submesothelial compact zone because of interstitial fibrosis (Tomino, 2012;de Lima et al, 2013). Activation of fibroblasts with expression of a-smooth muscle actin (a-SMA) is the cellular basis of interstitial fibrosis, which is accompanied by excessive deposition of extracellular matrix components, such as collagen I and fibronectin.…”

Section: Introductionmentioning

confidence: 99%

“…Activation of fibroblasts with expression of a-smooth muscle actin (a-SMA) is the cellular basis of interstitial fibrosis, which is accompanied by excessive deposition of extracellular matrix components, such as collagen I and fibronectin. Although the pathophysiologic role of fibroblasts in the peritoneum remains poorly understood, multiple factors and mechanisms, such as inflammation (Tomino, 2012;de Lima et al, 2013), neoangiogenesis (Sekiguchi et al, 2012), and activation of transforming growth factor-b1 (TGF-b1) signaling (Chegini, 2008;Liu et al, 2012), have been shown to contribute to this process. TGF-b1 exerts its biologic actions through activation of two downstream signaling molecules, Smad2/3.…”

Section: Introductionmentioning

confidence: 99%

Suramin Inhibits the Development and Progression of Peritoneal Fibrosis

Xiong

Liu

Lü

et al. 2014

The Journal of Pharmacology and Experimental Therapeutics

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Peritoneal fibrosis is one of the most serious complications in patients with peritoneal dialysis (PD) and is associated with the loss of peritoneal membrane ultrafiltration function. In this study, we investigated whether suramin, an inhibitor that blocks multiple growth factors by binding to their receptors, would prevent development of peritoneal fibrosis in a rat model. Rats were given a daily intraperitoneal injection of chlorhexidine gluconate (CG) for 3 weeks to induce peritoneal fibrosis. Administration of suramin at 5, 10, and 20 mg/kg dose-dependently attenuated peritoneal membrane thickening and expression of collagen I, fibronectin, and a-smooth muscle actin. Increased expression of transforming growth factor-b1 (TGF-b1) and phosphorylation of Smad3 was detected in fibrotic peritoneum and inhibited by suramin treatment. Suramin was also effective in blocking CG-induced phosphorylation of inhibitor of kB (IkB) and nuclear factor (NF)-kBp65, expression of several inflammatory cytokines, and infiltration of macrophages in the peritoneum. Moreover, suramin suppressed angiogenesis and expression of vascular endothelial growth factor, a molecule associated with angiogenesis in the injured peritoneum. Therefore, our results indicate that suramin treatment can effectively alleviate the development of peritoneal fibrosis by suppression of TGF-b1 signaling, inflammation, and angiogenesis, and suggest that suramin may have therapeutic potential for prevention of peritoneal fibrosis in PD patients.

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Beta‐catenin participates in dialysate‐induced peritoneal fibrosis via enhanced peritoneal cell epithelial‐to‐mesenchymal transition

Deng

Jin

et al. 2017

FEBS Open Bio

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Long‐term exposure to peritoneal dialysate with high glucose (HG) leads to peritoneal fibrosis and thus decreases dialysis efficiency. In this study, we explored the role of β‐catenin in this process. C57BL/6 mice received daily intraperitoneal injection with 10% of the body weight of saline (control), 4.25% glucose peritoneal dialysis fluid (PDF), or PDF combined with 5 mg·kg −1 of the β‐catenin inhibitor ICG‐001 (PDF+ICG) for 30 days. Also, mice peritoneal epithelial cells (mPECs) were cultured in 4.25% glucose (HG) or combined with 10 μ m ICG‐001 (HG+ICG) for 48 h. We found greater thickness of the parietal peritoneum in the PDF‐treated mice. Additionally, lower expression of E‐cadherin, higher expression of Vimentin, β‐catenin, and Snail, and activation of β‐catenin was observed in the mice and in HG‐treated mPECs, all of which were reversed by ICG‐001. The changes in E‐cadherin and Vimentin indicated occurrence of the epithelial‐to‐mesenchymal transition (EMT). Thus, β‐catenin signaling participates in the process of HG‐induced peritoneal fibrosis, and the EMT of peritoneal epithelial cells is one of the underlying mechanisms of this pathological change.

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Inflammation, neoangiogenesis and fibrosis in peritoneal dialysis

Cited by 57 publications

References 77 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

Suramin Inhibits the Development and Progression of Peritoneal Fibrosis

Beta‐catenin participates in dialysate‐induced peritoneal fibrosis via enhanced peritoneal cell epithelial‐to‐mesenchymal transition

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