Oral Astaxanthin Supplementation Prevents Peritoneal Fibrosis in Rats

Wakabayashi, Keiichi; Hamada, Chikuma; Kanda, Reo; Nakano, Takanori; Io, Hiroaki; Horikoshi, Satoshi; Tomino, Yasuhiko

doi:10.3747/pdi.2013.00317

Cited by 14 publications

(15 citation statements)

References 28 publications

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“…Increased macrophage infiltration in the submesothelial compact zone contributes to peritoneal fibrosis [ 13 , 40 ]. To determine whether HDAC6 was involved in this response, we first assessed the level of CD68, a biomarker of macrophages.…”

Section: Resultsmentioning

confidence: 99%

Histone deacetylase 6 inhibition counteracts the epithelial-mesenchymal transition of peritoneal mesothelial cells and prevents peritoneal fibrosis

Liu

et al. 2017

Oncotarget

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The role of histone deacetylase 6 (HDAC6) in peritoneal fibrosis remains unknown. In this study, we examined the effect of HDAC6 inhibition on the epithelial–mesenchymal transition (EMT) of peritoneal mesothelial cells and development of peritoneal fibrosis. Treatment with tubastatin A, a highly selective HDAC6 inhibitor, or silencing of HDAC6 with siRNA inhibited transforming growth factor β1-induced EMT, as evidenced by decreased expression of α-smooth muscle actin, collagen I and preserved expression of E-cadherin in cultured human peritoneal mesothelial cells. In a mouse model of peritoneal fibrosis induced by high glucose dialysate, administration of TA prevented thickening of the submesothelial region and decreased expression of collagen I and α-SMA. Mechanistically, tubastatin A treatment inhibited expression of TGF-β1 and phosphorylation of Smad-3, epidermal growth factor receptor, STAT3, and NF-κBp65. HDAC6 inhibition also suppressed production of multiple inflammatory cytokines/chemokines and reduced the infiltration of macrophages to the injured peritoneum. Moreover, tubastatin A was effective in inhibiting peritoneal increase of CD31(+) blood vessels and expression of vascular endothelial growth factor in the injured peritoneum. Collectively, these results suggest that HDAC6 inhibition can attenuate peritoneal fibrosis by inhibiting multiple pro-fibrotic signaling pathways, EMT, inflammation and blood vessel formation.

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Section: Resultsmentioning

confidence: 99%

Histone deacetylase 6 inhibition counteracts the epithelial-mesenchymal transition of peritoneal mesothelial cells and prevents peritoneal fibrosis

Liu

et al. 2017

Oncotarget

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“…We suppose that high glucose may, at least partly, play a crucial role as an oxidant, as reported elsewhere [ 11 – 13 ], which indicates room for improvement in the biocompatibility of the present standard solutions. Studies on clinical approaches to peritoneal protection have been limited so far [ 25 – 27 ].…”

Section: Discussionmentioning

confidence: 99%

Dissolved molecular hydrogen (H2) in Peritoneal Dialysis (PD) solutions preserves mesothelial cells and peritoneal membrane integrity

et al. 2017

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BackgroundPeritoneal dialysis (PD) is used as renal replacement therapy in patients with end-stage kidney disease. However, peritoneal membrane failure remains problematic and constitutes a critical cause of PD discontinuation. Recent studies have revealed the unique biological action of molecular hydrogen (H2) as an anti-oxidant, which ameliorates tissue injury. In the present study, we aimed to examine the effects of H2 on the peritoneal membrane of experimental PD rats.MethodEight-week-old male Sprague-Dawley rats were divided into the following groups (n = 8–11 each) receiving different test solutions: control group (no treatment), PD group (commercially available lactate-based neutral 2.5% glucose PD solution), and H2PD group (PD solution with dissolved H2 at 400 ppb). Furthermore, the influence of iron (FeCl3: 5 μM: inducer of oxidative cellular injury) in the respective PD solutions was also examined (Fe-PD and Fe-H2PD groups). The H2PD solution was manufactured by bathing a PD bag in H2-oversaturated water created by electrolysis of the water. Twenty mL of the test solutions were intraperitoneally injected once a day for 10 days. Parietal peritoneum samples and cells collected from the peritoneal surface following treatment with trypsin were subjected to analysis.ResultsIn the PD group as compared to controls, a mild but significant sub-mesothelial thickening was observed, with increase in the number of cells in the peritoneal surface tissue that were positive for apoptosis, proliferation and vimentin, as seen by immunostaining. There were significantly fewer of such changes in the H2PD group, in which there was a dominant presence of M2 (CD163+) macrophages in the peritoneum. The Fe-PD group showed a significant loss of mesothelial cells with sub-mesothelial thickening, these changes being ameliorated in the Fe-H2PD group.ConclusionH2-dissolved PD solutions could preserve mesothelial cells and peritoneal membrane integrity in PD rats. Clinical application of H2 in PD could be a novel strategy for protection of peritoneal tissue during PD treatment.

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“…Peritoneal fibrosis occurred by TGFβ via epitherial-mesenchymal transition [ 5 ] and TNF-α-induced interaction with TGF-β receptor is essential for TGF-β-dependent EMT at retinal pigment epithelial cells [ 39 ]. We previously reported peritoneal fibrosis (PF) induced by chlorhexidine (CH) was significantly suppressed in PF rats with AST supplemented diet, and the level of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and cytokine such as TNFα and TGFβ were suppressed in the peritoneum[ 11 ]. According to these results, we hypothesized that AST inhibits peritoneal fibrosis (PF) through suppression of TNF/TGF expression by quenching ROS.…”

Section: Discussionmentioning

confidence: 99%

“…posited that ROS production, in response to high concentrations of glucose, may contribute to several complications of diabetes mellitus [ 10 ]. We previously reported that the oral administration of astaxanthin (AST) diminished PF in chlorhexidine-induced PF rats [ 11 ]. AST is a prevalent carotenoid, with a polar structure at either end of the molecule, and a potent capacity for quenching ROS due to the presence of two oxygenated groups.…”

Section: Introductionmentioning

confidence: 99%

Scavenging of reactive oxygen species by astaxanthin inhibits epithelial–mesenchymal transition in high glucose-stimulated mesothelial cells

et al. 2017

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BackgroundHigh glucose concentrations influence the functional and structural development of the peritoneal membrane. We previously reported that the oral administration of astaxanthin (AST) suppressed peritoneal fibrosis (PF) as well as inhibited oxidative stress, inflammation, and epithelial–mesenchymal transition (EMT) of peritoneal mesothelial cells (PMCs) in a chlorhexidine-induced PF rat model. This suggests that oxidative stress induction of EMT is a key event during peritoneal damage. The present study evaluated the therapeutic effect of AST in suppressing EMT, in response to glucose-induced oxidative stress.MethodsTemperature-sensitive mesothelial cells (TSMCs) were cultured in the presence or absence of AST and then treated with 140 mM glucose for 3 or 12 hours. Expression levels of TNF-α, TGF-β, and VEGF were determined at the mRNA and protein levels, and nuclear factor kappa B (NF-κB) activity was evaluated. We measured NO2−/NO3− concentrations in cellular supernatants and determined 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels in mitochondrial and nuclear DNA. The expressions of E-cadherin and alpha-smooth muscle actin (α-SMA) were evaluated by double immunofluorescence and protein levels.ResultsHigh glucose concentrations induced overproduction of reactive oxidative species (ROS), increasing 8-OHdG mitochondrial DNA and cytokine levels. The NF-κB pathway was activated in response to high glucose concentrations, whereas de novo α-SMA expression was observed with decreased E-cadherin expression. AST treatment attenuated ROS production, inflammatory cytokine production, NF-κB activation, and EMT.ConclusionThe findings of the present study indicate that AST may have an anti-EMT effect due to anti-oxidative and anti-inflammatory activities by scavenging glucose-induced ROS from mitochondria in PMCs. AST may be an efficacious treatment for PF.

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Oral Astaxanthin Supplementation Prevents Peritoneal Fibrosis in Rats

Cited by 14 publications

References 28 publications

Histone deacetylase 6 inhibition counteracts the epithelial-mesenchymal transition of peritoneal mesothelial cells and prevents peritoneal fibrosis

Histone deacetylase 6 inhibition counteracts the epithelial-mesenchymal transition of peritoneal mesothelial cells and prevents peritoneal fibrosis

Dissolved molecular hydrogen (H2) in Peritoneal Dialysis (PD) solutions preserves mesothelial cells and peritoneal membrane integrity

Scavenging of reactive oxygen species by astaxanthin inhibits epithelial–mesenchymal transition in high glucose-stimulated mesothelial cells

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