Alterations in proteoglycan components and histopathology of the peritoneum in uraemic and peritoneal dialysis (PD) patients

Osada, Shiwori; Hamada, Chikuma; Shimaoka, Tetsutaro; Kaneko, Kayo; Horikoshi, Satoshi; Tomino, Yasuhiko

doi:10.1093/ndt/gfp268

Cited by 29 publications

(29 citation statements)

References 22 publications

(19 reference statements)

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“…Macrophages are one of the main cell populations mediating inflammation, and play an important role in innate and adaptive immune responses (24,25). Osada et al proved that CD68-positive cells (macrophages) in the peritoneum were marked in long-term PD patient samples (26). Our study showed that macrophages were significantly increased in the peritoneum of rats administered daily i.p.…”

Section: Discussionsupporting

confidence: 49%

Characterization of infiltrating macrophages in high glucose-induced peritoneal fibrosis in rats

Jiang

Liu

et al. 2012

Mol Med Report

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Abstract. Alternatively activated macrophages (M2 macrophages) are involved in tissue remodeling and fibrosis, but their effects on peritoneal fibrosis (PF) induced by high glucose peritoneal dialysate have yet to be fully established. In this study, PF was induced in male Sprague-Dawley rats by intraperitoneal injection with Lactate-G4.25% dialysate (20 ml/rat/day) for 4 weeks. Control rats were given an intraperitoneal injection with saline. Establishment of the PF model was verified by Masson's trichrome and H&E staining. M1 macrophages (co-localization of CD68 and CCr7) and M2 macrophages (co-localization of CD68 and CD206) was assayed by immunofluorescence and immunohistochemistry. The levels of dialysate cytokines driving macrophage differentiation (including IFN-γ, IL-2 and IL-4) were detected by ELISA. The expression of transforming growth factor (TGF)-β, p-Smad3, p-Smad2/3 and Smad7 in M2 macrophages (co-localization of CD68, CD206 and TGF-β, or p-Smad3, or p-Smad2/3, or Smad7) was measured by immunofluorescence. We found that PF rats had significantly thicker peritoneal membranes compared to control rats, indicating the successful establishment of our PF model. Compared to controls, PF rats had more peritoneal macrophages (CD68 + cells), more peritoneal M1 macrophages and a greater percentage of peritoneal M2 macrophages. PF rats also had significantly greater levels of dialysate cytokine IL-4, which promotes differentiation to M2 macrophages, higher expression levels of TGF-β in peritoneal M2 macrophages, upregulation of phosphorylated Smad3 and Smad2/3, and downregulation of Smad7 in peritoneal M2 macrophages. Our results indicate that M2 macrophages may play an important role in PF induced by high glucose, and that the cytokine environment in the abdominal cavities of PF rats promotes differentiation to M2 macrophages. The function of M2 macrophages in PF may be related to the TGF-β/Smad signaling pathways.

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Section: Discussionsupporting

confidence: 49%

Characterization of infiltrating macrophages in high glucose-induced peritoneal fibrosis in rats

Jiang

Liu

et al. 2012

Mol Med Report

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“…Since versican is a component of the tumor inflammatory response facilitating lung metastases (50) and has been linked to macrophage-mediated inflammatory vascular disease (9,10,12,14,29,38,(51)(52)(53)(54), we hypothesized that GDI2 might suppress lung metastasis through downregulation of versican, in turn leading to a reduction of macrophage lung infiltration. We compared macrophage infiltration within and adjacent to metastatic lung foci that developed after tail-vein injection of GFP and GDI2 cells and found a reduction in mice injected with GDI2 cells compared with GFP controls ( Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

RhoGDI2 suppresses lung metastasis in mice by reducing tumor versican expression and macrophage infiltration

Said¹,

Sänchez‐Carbayo²,

Smith³

et al. 2012

J. Clin. Invest.

130

110

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Half of patients with muscle-invasive bladder cancer develop metastatic disease, and this is responsible for most of the deaths from this cancer. Low expression of RhoGTP dissociation inhibitor 2 (RhoGDI2; also known as ARHGDIB and Ly-GDI) is associated with metastatic disease in patients with muscle-invasive bladder cancer. Moreover, a reduction in metastasis is observed upon reexpression of RhoGDI2 in xenograft models of metastatic cancer. Here, we show that RhoGDI2 suppresses lung metastasis in mouse models by reducing the expression of isoforms V1 and V3 of the proteoglycan versican (VCAN; also known as chondroitin sulfate proteoglycan 2 [CSPG2]). In addition, we found that high versican levels portended poor prognosis in patients with bladder cancer. The functional importance of tumor expression of versican in promoting metastasis was established in in vitro and in vivo studies in mice that implicated a role for the chemokine CCL2 (also known as MCP1) and macrophages. Further analysis indicated that RhoGDI2 suppressed metastasis by altering inflammation in the tumor microenvironment. In summary, we demonstrate what we believe to be a new mechanism of metastasis suppression that works by reducing host responses that promote metastatic colonization of the lung. Therapeutic targeting of these interactions may provide a novel adjuvant strategy for delaying the appearance of clinical metastasis in patients. IntroductionOne-half of patients with muscle-invasive (MI) urothelial cancer (UC) of the bladder develop distant metastases, even after radical surgery of the primary tumors. We identified RhoGTP dissociation inhibitor 2 (RhoGDI2; also known as ARHGDIB and Ly-GDI, and abbreviated herein as GDI2) as an invasion and metastasis suppressor in human bladder cancer cell lines (1) and have shown that its expression is inversely associated with clinical outcome after treatment of MI tumors (2). Independently, in comparative gene expression profiling of invasive bladder cancer cell lines and human MI UC samples, we identified versican (VCAN; also known as chondroitin sulfate proteoglycan 2, [CSPG2]) as highly expressed in invasive and metastatic cancers (3).Versican is a highly conserved structural component of the ECM that is involved in neuronal development (4-8), the inflammatory phase of pulmonary-vascular diseases, atherosclerosis (9-12), and the invasive and metastatic signatures of many cancers (13-25). Four isoforms or spliced variants have been reported for versican, and the roles of V0, V1, and V3 and to a lesser extent V2 isoforms are recognized in cancer, vascular disease, and neuronal development (detailed in refs. 8, 26, 27, and the references cited therein). These isoforms contribute to proliferative, adhesive, and migratory states of tumor cells and modulate their interactions with stroma in the tumor microenvironment (26,28,29).Versican expression is regulated by cytokines, chemokines, and hypoxia (6, 7, 9-12, 21, 26, 29-36) via transcription factors such as TCF-4, SP-1, AP-1, and p53, which have bin...

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“…Giebel et al have reported that elevated MMP-2 or MMP-9 expression in the retina may facilitate an increase in vascular permeability by degrading occludin, the tight junction protein of endothelial or epithelial cells [32]. Osada the blood vessels in the peritoneal tissues from long-term PD patients [33]. In PD, destruction of the tight junction of endothelial cells by MMP-2 may result in hyperpermeability of the peritoneum.…”

Section: Mmps As Peritoneal Injury Markers In Clinical Diagnosismentioning

confidence: 99%

“…[44], which may explain why drainage levels of MMP-2 reflects the peritoneal transport ratio. Activated mesenchymal cells, such as myofibroblasts or fibroblasts, synthesize ECM proteins or migrate during the disassemble of ECM of the peritoneum by MMP-2 or other proteinases [8][9][10][11][12]33]. Presence of excessive ECM proteins, such as collagen, leads to peritoneal fibrosis with peritoneal thickening and promotes the production of MMP-2 by myofibroblasts [9].…”

Section: Production Of Mmp-2 In the Peritoneummentioning

confidence: 99%

“…Presence of excessive ECM proteins, such as collagen, leads to peritoneal fibrosis with peritoneal thickening and promotes the production of MMP-2 by myofibroblasts [9]. In addition, neomicrovascularization may occur while ECM is being degraded by MMP-2 produced by activated endothelial cells in the microvasculature [10,12,33]. According to the results of D/S ratio analysis, most MMP-2 in the peritoneal effluent is not transported from the circulation [26].…”

Section: Production Of Mmp-2 In the Peritoneummentioning

confidence: 99%

See 1 more Smart Citation

Matrix Metalloproteinases Cause Peritoneal Injury in Peritoneal Dialysis

Hirahara¹,

Akimoto²,

Morishita³

et al. 2011

Progress in Peritoneal Dialysis

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Alterations in proteoglycan components and histopathology of the peritoneum in uraemic and peritoneal dialysis (PD) patients

Cited by 29 publications

References 22 publications

Characterization of infiltrating macrophages in high glucose-induced peritoneal fibrosis in rats

Characterization of infiltrating macrophages in high glucose-induced peritoneal fibrosis in rats

RhoGDI2 suppresses lung metastasis in mice by reducing tumor versican expression and macrophage infiltration

Matrix Metalloproteinases Cause Peritoneal Injury in Peritoneal Dialysis

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