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1
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Yamakawa Y, Mihara T, Hori M. Intestinal Dysmotility and Associated Disorders in Intestinal Muscle of Methylglyoxal-Treated Mice. Neurogastroenterol Motil 2025:e70068. [PMID: 40317859 DOI: 10.1111/nmo.70068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 03/31/2025] [Accepted: 04/18/2025] [Indexed: 05/07/2025]
Abstract
BACKGROUND Peritoneal dialysis (PD) is a renal replacement therapy approach to treat end-stage renal failure. However, complications such as gastrointestinal dysmotility occur in patients undergoing PD, and the mechanisms underlying these complications have not been elucidated. We hypothesized that inflammation and dysfunction of the interstitial cells of Cajal (ICC) contribute to the PD-induced gastrointestinal dysmotility. METHODS Mice were intraperitoneally administered a dialysate containing methylglyoxal (40 mM) every other day for 2 weeks to mimic the gastrointestinal complications in patients undergoing long-term PD. The gastrointestinal transit capacity was evaluated using fluorescent dyes that were forcibly administered orally. To evaluate the inflammation and function of the ICC in the intestinal muscles, we performed real-time polymerase chain reaction and immunohistochemical staining and measured spontaneous contractions ex vivo. KEY RESULTS The intestinal transit capacity was significantly reduced in the methylglyoxal-treated group compared to that in the control group. In the inflammatory evaluation, the number of neutrophils and macrophages in the intestinal muscles significantly increased in the methylglyoxal-treated group compared to the control group. Moreover, the mRNA expression levels of Tnf, Il1b, and Il6 were upregulated in the intestinal muscle from the methylglyoxal-treated group. The mRNA expression of Kit, an interstitial cell of Cajal marker, was significantly decreased in the methylglyoxal-treated group. In addition, the frequency of spontaneous contractions, an index of ICC function, was decreased in the methylglyoxal-treated group. CONCLUSIONS AND INFERENCE Our data suggest that the PD-induced gastrointestinal dysmotility might be due to inflammation and dysfunction of the ICC in intestinal muscles.
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Affiliation(s)
- Yuki Yamakawa
- Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Taiki Mihara
- Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Masatoshi Hori
- Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan
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Li J, Liu Y, Liu J. A review of research progress on mechanisms of peritoneal fibrosis related to peritoneal dialysis. Front Physiol 2023; 14:1220450. [PMID: 37817984 PMCID: PMC10560738 DOI: 10.3389/fphys.2023.1220450] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 09/13/2023] [Indexed: 10/12/2023] Open
Abstract
Peritoneal dialysis (PD) is an effective alternative treatment for patients with end-stage renal disease (ESRD) and is increasingly being adopted and promoted worldwide. However, as the duration of peritoneal dialysis extends, it can expose problems with dialysis inadequacy and ultrafiltration failure. The exact mechanism and aetiology of ultrafiltration failure have been of great concern, with triggers such as biological incompatibility of peritoneal dialysis solutions, uraemia toxins, and recurrent intraperitoneal inflammation initiating multiple pathways that regulate the release of various cytokines, promote the transcription of fibrosis-related genes, and deposit extracellular matrix. As a result, peritoneal fibrosis occurs. Exploring the pathogenic factors and molecular mechanisms can help us prevent peritoneal fibrosis and prolong the duration of Peritoneal dialysis.
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Affiliation(s)
- Jin’e Li
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Yinghong Liu
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Jianping Liu
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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3
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Su HY, Yang JJ, Zou R, An N, Chen XC, Yang C, Yang HJ, Yao CW, Liu HF. Autophagy in peritoneal fibrosis. Front Physiol 2023; 14:1187207. [PMID: 37256065 PMCID: PMC10226653 DOI: 10.3389/fphys.2023.1187207] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 05/03/2023] [Indexed: 06/01/2023] Open
Abstract
Peritoneal dialysis (PD) is a widely accepted renal replacement therapy for patients with end-stage renal disease (ESRD). Morphological and functional changes occur in the peritoneal membranes (PMs) of patients undergoing long-term PD. Peritoneal fibrosis (PF) is a common PD-related complication that ultimately leads to PM injury and peritoneal ultrafiltration failure. Autophagy is a cellular process of "self-eating" wherein damaged organelles, protein aggregates, and pathogenic microbes are degraded to maintain intracellular environment homeostasis and cell survival. Growing evidence shows that autophagy is involved in fibrosis progression, including renal fibrosis and hepatic fibrosis, in various organs. Multiple risk factors, including high-glucose peritoneal dialysis solution (HGPDS), stimulate the activation of autophagy, which participates in PF progression, in human peritoneal mesothelial cells (HPMCs). Nevertheless, the underlying roles and mechanisms of autophagy in PF progression remain unclear. In this review, we discuss the key roles and potential mechanisms of autophagy in PF to offer novel perspectives on future therapy strategies for PF and their limitations.
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Steenbeke M, Speeckaert R, Desmedt S, Glorieux G, Delanghe JR, Speeckaert MM. The Role of Advanced Glycation End Products and Its Soluble Receptor in Kidney Diseases. Int J Mol Sci 2022; 23:ijms23073439. [PMID: 35408796 PMCID: PMC8998875 DOI: 10.3390/ijms23073439] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 03/20/2022] [Accepted: 03/21/2022] [Indexed: 02/06/2023] Open
Abstract
Patients with chronic kidney disease (CKD) are more prone to oxidative stress and chronic inflammation, which may lead to an increase in the synthesis of advanced glycation end products (AGEs). Because AGEs are mostly removed by healthy kidneys, AGE accumulation is a result of both increased production and decreased kidney clearance. On the other hand, AGEs may potentially hasten decreasing kidney function in CKD patients, and are independently related to all-cause mortality. They are one of the non-traditional risk factors that play a significant role in the underlying processes that lead to excessive cardiovascular disease in CKD patients. When AGEs interact with their cell-bound receptor (RAGE), cell dysfunction is initiated by activating nuclear factor kappa-B (NF-κB), increasing the production and release of inflammatory cytokines. Alterations in the AGE-RAGE system have been related to the development of several chronic kidney diseases. Soluble RAGE (sRAGE) is a decoy receptor that suppresses membrane-bound RAGE activation and AGE-RAGE-related toxicity. sRAGE, and more specifically, the AGE/sRAGE ratio, may be promising tools for predicting the prognosis of kidney diseases. In the present review, we discuss the potential role of AGEs and sRAGE as biomarkers in different kidney pathologies.
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Affiliation(s)
- Mieke Steenbeke
- Nephrology Unit, Department of Internal Medicine and Pediatrics, Ghent University Hospital, 9000 Ghent, Belgium; (M.S.); (S.D.); (G.G.)
| | - Reinhart Speeckaert
- Department of Dermatology, Ghent University Hospital, 9000 Ghent, Belgium;
- Research Foundation Flanders, 1000 Brussels, Belgium
| | - Stéphanie Desmedt
- Nephrology Unit, Department of Internal Medicine and Pediatrics, Ghent University Hospital, 9000 Ghent, Belgium; (M.S.); (S.D.); (G.G.)
| | - Griet Glorieux
- Nephrology Unit, Department of Internal Medicine and Pediatrics, Ghent University Hospital, 9000 Ghent, Belgium; (M.S.); (S.D.); (G.G.)
| | - Joris R. Delanghe
- Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium;
| | - Marijn M. Speeckaert
- Nephrology Unit, Department of Internal Medicine and Pediatrics, Ghent University Hospital, 9000 Ghent, Belgium; (M.S.); (S.D.); (G.G.)
- Research Foundation Flanders, 1000 Brussels, Belgium
- Correspondence:
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5
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Zhang J, Chen Y, Chen T, Miao B, Tang Z, Hu X, Luo Y, Zheng T, Na N. Single-cell transcriptomics provides new insights into the role of fibroblasts during peritoneal fibrosis. Clin Transl Med 2021; 11:e321. [PMID: 33784014 PMCID: PMC7908046 DOI: 10.1002/ctm2.321] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 01/25/2021] [Accepted: 01/25/2021] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND The contributions of various types of cell populations in dialysis-related peritoneal fibrosis are poorly understood. Single-cell RNA sequencing brings single-cell level resolution to the analysis of cellular transcriptomics, which provides a new way to further characterize the distinct roles and functional states of each cell population during peritoneal fibrosis. METHODS Single-cell transcriptomics from normal peritoneal tissues of six patients, from effluent of patients with short-term peritoneal dialysis (less than 2 weeks, n = 6), and from long-term peritoneal dialysis patients (more than 6 years, n = 4) were analyzed. RESULTS We identified a distinct cell component between samples among different groups. Functional analysis of the differentially expressed genes identified cell type specific biological processes relevant to different fibrosis stages. Well-known key molecular mechanisms participating in the pathophysiology of peritoneal fibrosis were vitrified, and some of them were found to be restricted to specific cell types. Gradually growing enrichment of PI3K/AKT/mTOR pathway and impairment of oxidative phosphorylation in mesothelial cells and fibroblasts were found from healthy control, short-term dialysis, to long-term dialysis, respectively. The fibroblasts' population obtained from the patients, who received peritoneal dialysis, showed a functional characteristic of immune-chemotaxis and immune response, which was characterized by broadly significant increase in the expression of interleukins, chemokines, cytokines, and human leukocyte antigens. Furthermore, we described the intercellular crosstalk networks based on receptor-ligand interactions, and highlighted a central role of fibroblasts in regulating the key mechanisms of peritoneal fibrosis through crosstalk with other cells. CONCLUSIONS In summary, despite describing information for fibrogenic molecular mechanisms in the resolution level of individual cell populations, this work identifies the significant functional evolution of fibroblasts during peritoneal fibrosis. This study also reveals the intercellular receptor-ligand interactions in which the fibroblasts serve as a major node, eventually providing new insights into the role of fibroblasts during disease pathogenesis.
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Affiliation(s)
- Jinhua Zhang
- Department of Kidney TransplantationThe Third Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Yuxian Chen
- Department of Joint SurgeryThe Third Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Tufeng Chen
- Department of Gastrointestinal SurgeryThe Third Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Bin Miao
- Department of Kidney TransplantationThe Third Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Zuofu Tang
- Department of Kidney TransplantationThe Third Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Xiao Hu
- Department of Kidney TransplantationThe Third Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - You Luo
- Department of Kidney TransplantationThe Third Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Tong Zheng
- Department of Kidney TransplantationThe Third Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Ning Na
- Department of Kidney TransplantationThe Third Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
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Abstract
♦ Background The introduction of peritoneal dialysis (PD) as a modality of renal replacement therapy has provoked much interest in the biology of the peritoneal mesothelial cell. Mesothelial cells isolated from omental tissue have immunohistochemical markers that are identical to those of mesothelial stem cells, and omental mesothelial cells can be cultivated in vitro to study changes to their biologic functions in the setting of PD. ♦ Method The present article describes the structure and function of mesothelial cells in the normal peritoneum and details the morphologic changes that occur after the introduction of PD. Furthermore, this article reviews the literature of mesothelial cell culture and the limitations of in vitro studies. ♦ Results The mesothelium is now considered to be a dynamic membrane that plays a pivotal role in the homeostasis of the peritoneal cavity, contributing to the control of fluid and solute transport, inflammation, and wound healing. These functional properties of the mesothelium are compromised in the setting of PD. Cultures of peritoneal mesothelial cells from omental tissue provide a relevant in vitro model that allows researchers to assess specific molecular pathways of disease in a distinct population of cells. Structural and functional attributes of mesothelial cells are discussed in relation to long-term culture, proliferation potential, age of tissue donor, use of human or animal in vitro models, and how the foregoing factors may influence in vitro data. ♦ Conclusions The ability to propagate mesothelial cells in culture has resulted, over the past two decades, in an explosion of mesothelial cell research pertaining to PD and peritoneal disorders. Independent researchers have highlighted the potential use of mesothelial cells as targets for gene therapy or transplantation in the search to provide therapeutic strategies for the preservation of the mesothelium during chemical or bacterial injury.
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Affiliation(s)
- Susan Yung
- Department of Medicine, University of Hong Kong, Hong Kong SAR, PR China
| | - Chan Tak Mao
- Department of Medicine, University of Hong Kong, Hong Kong SAR, PR China
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7
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Abstract
During peritoneal dialysis, peritoneal cells are repeatedly exposed to a non-physiologic hypertonic environment with high glucose content and low pH. Current sterile dialysis solutions cause inflammation in the submesothelial compact zone, leading to fibrosis, angiogenesis, and, eventually, ultrafiltration failure. Although the normal interstitium separates the peritoneal microvasculature from the dialysis fluid and makes transperitoneal transport less efficient, changes in the submesothelial compact zone can result in progressive increases in solute transfer and ultrafiltration diminution. This peritoneal dysfunction will further be amplified with the development of an epithelial-to-mesenchymal transition of mesothelial cells and dissipation of the osmotic driving force through the increased area and solute transport that accompany neoangiogenesis of the submesothelial microvasculature. The alteration of the peritoneal membrane can be further aggravated by peritonitis, advanced glycation end-products, and glucose degradation products. Furthermore, new data are emerging to support a proinflammatory role for peritoneal adipocytes.
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Affiliation(s)
- Kar Neng Lai
- Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, PR China
| | - Sydney C.W. Tang
- Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, PR China
| | - Joseph C.K. Leung
- Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, PR China
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Wang Y, Shi Y, Tao M, Zhuang S, Liu N. Peritoneal fibrosis and epigenetic modulation. Perit Dial Int 2020; 41:168-178. [PMID: 32662737 DOI: 10.1177/0896860820938239] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Peritoneal dialysis (PD) is an effective treatment for patients with end-stage renal disease. However, peritoneal fibrosis (PF) is a common complication that ultimately leads to ultrafiltration failure and discontinuation of PD after long-term PD therapy. There is currently no effective therapy to prevent or delay this pathologic process. Recent studies have reported epigenetic modifications involved in PF, and accumulating evidence suggests that epigenetic therapies may have the potential to prevent and treat PF clinically. The major epigenetic modifications in PF include DNA methylation, histone modification, and noncoding RNAs. The mechanisms of epigenetic regulation in PF are complex, predominantly involving modification of signaling molecules, transcriptional factors, and genes. This review will describe the mechanisms of epigenetic modulation in PF and discuss the possibility of targeting them to prevent and treat this complication.
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Affiliation(s)
- Yi Wang
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, China
| | - Yingfeng Shi
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, China
| | - Min Tao
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, China
| | - Shougang Zhuang
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, China.,Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI, USA
| | - Na Liu
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, China
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Reprogramming of Mesothelial-Mesenchymal Transition in Chronic Peritoneal Diseases by Estrogen Receptor Modulation and TGF-β1 Inhibition. Int J Mol Sci 2020; 21:ijms21114158. [PMID: 32532126 PMCID: PMC7312018 DOI: 10.3390/ijms21114158] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 05/31/2020] [Accepted: 06/04/2020] [Indexed: 12/14/2022] Open
Abstract
In chronic peritoneal diseases, mesothelial-mesenchymal transition is determined by cues from the extracellular environment rather than just the cellular genome. The transformation of peritoneal mesothelial cells and other host cells into myofibroblasts is mediated by cell membrane receptors, Transforming Growth Factor β1 (TGF-β1), Src and Hypoxia-inducible factor (HIF). This article provides a narrative review of the reprogramming of mesothelial mesenchymal transition in chronic peritoneal diseases, drawing on the similarities in pathophysiology between encapsulating peritoneal sclerosis and peritoneal metastasis, with a particular focus on TGF-β1 signaling and estrogen receptor modulators. Estrogen receptors act at the cell membrane/cytosol as tyrosine kinases that can phosphorylate Src, in a similar way to other receptor tyrosine kinases; or can activate the estrogen response element via nuclear translocation. Tamoxifen can modulate estrogen membrane receptors, and has been shown to be a potent inhibitor of mesothelial-mesenchymal transition (MMT), peritoneal mesothelial cell migration, stromal fibrosis, and neoangiogenesis in the treatment of encapsulating peritoneal sclerosis, with a known side effect and safety profile. The ability of tamoxifen to inhibit the transduction pathways of TGF-β1 and HIF and achieve a quiescent peritoneal stroma makes it a potential candidate for use in cancer treatments. This is relevant to tumors that spread to the peritoneum, particularly those with mesenchymal phenotypes, such as colorectal CMS4 and MSS/EMT gastric cancers, and pancreatic cancer with its desmoplastic stroma. Morphological changes observed during mesothelial mesenchymal transition can be treated with estrogen receptor modulation and TGF-β1 inhibition, which may enable the regression of encapsulating peritoneal sclerosis and peritoneal metastasis.
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Van Laecke S, Veys N, Verbeke F, Vanholder R, Van Biesen W. The Fate of Older Diabetic Patients on Peritoneal Dialysis: Myths and Mysteries and Suggestions for Further Research. Perit Dial Int 2020. [DOI: 10.1177/089686080702700602] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
The outcome of older and especially of female diabetic patients appears to be worse on peritoneal dialysis (PD) than on hemodialysis (HD). This opinion is based mostly on data coming from the USA, whereas data from other regions seem to give a more balanced picture. The questions arise whether indeed outcome is worse in this patient group, and what might be the underlying reasons for this; further research to unravel this phenomenon is warranted. This review proposes several suggestions for further exploration. The observed differences in outcome might be attributable to differences in treatment practices and experience with PD versus HD. As cardiovascular mortality is a major killer in end-stage renal disease patients, differences in fluid homeostasis and how it is achieved are potential explanations. Fluid balance is potentially more difficult to obtain in PD patients, especially as in the past it was spuriously suggested that fluid restriction was less important in PD patients. PD and HD might also have different impacts on factors related to inflammation, insulin resistance, and hormone balance. The adipocytokine network is of special interest in this respect. It is also possible that bias introduced by the way we measure body composition might have a more negative impact on PD than on HD patients. Finally, it still is not fully established that if diabetic patients are treated appropriately, their outcome on PD is worse than that on HD; further observational trials in this respect are needed. All these topics require further clarification and investigation.
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Affiliation(s)
- Steven Van Laecke
- Renal Division, Department of Internal Medicine, University Hospital Ghent, Belgium
| | - Nic Veys
- Renal Division, Department of Internal Medicine, University Hospital Ghent, Belgium
| | - Francis Verbeke
- Renal Division, Department of Internal Medicine, University Hospital Ghent, Belgium
| | - Raymond Vanholder
- Renal Division, Department of Internal Medicine, University Hospital Ghent, Belgium
| | - Wim Van Biesen
- Renal Division, Department of Internal Medicine, University Hospital Ghent, Belgium
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11
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Hirahara I, Kusano E, Jin D, Takai S. Hypermetabolism of glutathione, glutamate and ornithine via redox imbalance in methylglyoxal-induced peritoneal injury rats. J Biochem 2020; 167:185-194. [PMID: 31593282 DOI: 10.1093/jb/mvz077] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Accepted: 09/17/2019] [Indexed: 11/13/2022] Open
Abstract
Peritoneal dialysis (PD) is a blood purification treatment for patients with reduced renal function. However, the peritoneum is exposed to oxidative stress during PD and long-term PD results in peritoneal damage, leading to the termination of PD. Methylglyoxal (MGO) contained in commercial PD fluids is a source of strong oxidative stress. The aim of this study was to clarify the mechanism of MGO-induced peritoneal injury using metabolome analysis in rats. We prepared peritoneal fibrosis rats by intraperitoneal administration of PD fluids containing MGO for 21 days. As a result, MGO-induced excessive proliferation of mesenchymal cells with an accumulation of advanced glycation end-products (AGEs) at the surface of the thickened peritoneum in rats. The effluent levels of methionine sulfoxide, an oxidative stress marker and glutathione peroxidase activity were increased in the MGO-treated rats. The levels of glutathione, glutamate, aspartate, ornithine and AGEs were also increased in these rats. MGO upregulated the gene expression of transporters and enzymes related to the metabolism of glutathione, glutamate and ornithine in the peritoneum. These results suggest that MGO may induce peritoneal injury with mesenchymal cell proliferation via increased redox metabolism, directly or through the formation of AGEs during PD.
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Affiliation(s)
- Ichiro Hirahara
- Department of Innovative Medicine, Graduate School of Medicine, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 568-8686
| | - Eiji Kusano
- JCHO Utsunomiya Hospital, 11-17 Minamitakasago-chou, Utsunomiya, Tochigi 321-0143, Japan
| | - Denan Jin
- Department of Innovative Medicine, Graduate School of Medicine, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 568-8686
| | - Shinji Takai
- Department of Innovative Medicine, Graduate School of Medicine, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 568-8686
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Kang SH, Kim SW, Kim KJ, Cho KH, Park JW, Kim CD, Do JY. Effects of tranilast on the epithelial-to-mesenchymal transition in peritoneal mesothelial cells. Kidney Res Clin Pract 2019; 38:472-480. [PMID: 31554027 PMCID: PMC6913598 DOI: 10.23876/j.krcp.19.049] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 07/03/2019] [Accepted: 07/09/2019] [Indexed: 12/17/2022] Open
Abstract
Background We investigated the effects of tranilast on epithelial-to-mesenchymal transition (EMT) in an animal model and on the EMT signaling pathway in human peritoneal mesothelial cells (HPMCs). Methods We performed in vitro studies (cytotoxicity, cell morphology, and western blot analyses) on HPMCs from human omenta, along with in vivo studies (peritoneal membrane function and morphometric and immunohistochemical analyses) on Sprague Dawley rats. Thirty-two rats were divided into three groups: control (C) group (peritoneal dialysis [PD] catheter but not infused with dialysate), PD group (4.25% glucose-containing dialysate), and PD + tranilast group (4.25% glucose-containing dialysate along with tranilast). Results In in vitro experiments, transforming growth factor-beta 1 (TGF-β1) increased α-smooth muscle actin and Snail expression and reduced E-cadherin expression in HPMCs. TGF-β1 also reduced cell contact, induced a fibroblastoid morphology, and increased phosphorylation of Akt, Smad2, and Smad3 in HPMCs. Tranilast significantly inhibited TGF-β1-induced EMT and attenuated these morphological changes in HPMCs. In in vivo studies, after 6 weeks of experimental PD, the peritoneal membrane was significantly thicker in the PD group than in the C group. Tranilast protected against PD-induced glucose mass transfer change and histopathological changes in rats. Conclusion Tranilast prevented EMT both in HPMCs triggered with TGF-β1 and in rats with PD-induced peritoneal fibrosis. Thus, tranilast may be considered a therapeutic intervention that enables long-term PD by regulating TGF-β1 signaling pathways.
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Affiliation(s)
- Seok Hui Kang
- Division of Nephrology, Department of Internal Medicine, Yeungnam University Medical Center, Daegu, Republic of Korea
| | - Sang Woon Kim
- Division of Gastro-Enterology, Department of Surgery, Yeungnam University Hospital, Daegu, Republic of Korea
| | - Keuk Jun Kim
- Department of Biomedical Laboratory Science, Daekyeung University, Gyeongsan, Republic of Korea
| | - Kyu Hyang Cho
- Division of Nephrology, Department of Internal Medicine, Yeungnam University Medical Center, Daegu, Republic of Korea
| | - Jong Won Park
- Division of Nephrology, Department of Internal Medicine, Yeungnam University Medical Center, Daegu, Republic of Korea
| | - Chan-Duck Kim
- Division of Nephrology, Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Jun Young Do
- Division of Nephrology, Department of Internal Medicine, Yeungnam University Medical Center, Daegu, Republic of Korea
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13
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Zhu W, Zhang X, Gao K, Wang X. Effect of astragaloside IV and the role of nuclear receptor RXRα in human peritoneal mesothelial cells in high glucose‑based peritoneal dialysis fluids. Mol Med Rep 2019; 20:3829-3839. [PMID: 31485615 PMCID: PMC6755149 DOI: 10.3892/mmr.2019.10604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 07/25/2019] [Indexed: 12/03/2022] Open
Abstract
Peritoneal fibrosis is a serious complication that can occur during peritoneal dialysis (PD), which is primarily caused by damage to peritoneal mesothelial cells (PMCs). The onset of peritoneal fibrosis is delayed or inhibited by promoting PMC survival and inhibiting PMC epithelial-to-mesenchymal transition (EMT). In the present study, the effect of astragaloside IV and the role of the nuclear receptor retinoid X receptor-α (RXRα) in PMCs in high glucose-based PD fluids was investigated. Human PMC HMrSV5 cells were transfected with RXRα short hairpin RNA (shRNA), or an empty vector, and then treated with PD fluids and astragaloside IV. Cell viability, apoptosis and EMT were examined using the Cell Counting Kit-8 assay and flow cytometry, and by determining the levels of caspase-3, E-cadherin and α-smooth muscle actin (α-SMA) via western blot analysis. Cell viability and apoptosis were increased, as were the levels of E-cadherin in HMrSV5 cells following treatment with PD fluid. The protein levels of α-SMA and caspase-3 were increased by treatment with PD fluid. Exposure to astragaloside IV inhibited these changes; however, astragaloside IV did not change cell viability, apoptosis, E-cadherin or α-SMA levels in HMrSV5 cells under normal conditions. Transfection of HMrSV5 cells with RXRα shRNA resulted in decreased viability and E-cadherin expression, and increased apoptosis and α-SMA levels, in HMrSV5 cells treated with PD fluids and co-treated with astragaloside IV or vehicle. These results suggested that astragaloside IV increased cell viability, and inhibited apoptosis and EMT in PMCs in PD fluids, but did not affect these properties of PMCs under normal condition. Thus, the present study suggested that RXRα is involved in maintaining viability, inhibiting apoptosis and reducing EMT of PMCs in PD fluid.
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Affiliation(s)
- Weiwei Zhu
- Department of Nephrology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, P.R. China
| | - Xin Zhang
- Department of Urology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, P.R. China
| | - Kun Gao
- Department of Nephrology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, P.R. China
| | - Xufang Wang
- Department of Nephrology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, P.R. China
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14
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Kinashi H, Toda N, Sun T, Nguyen TQ, Suzuki Y, Katsuno T, Yokoi H, Aten J, Mizuno M, Maruyama S, Yanagita M, Goldschmeding R, Ito Y. Connective tissue growth factor is correlated with peritoneal lymphangiogenesis. Sci Rep 2019; 9:12175. [PMID: 31434958 PMCID: PMC6704065 DOI: 10.1038/s41598-019-48699-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 08/07/2019] [Indexed: 12/04/2022] Open
Abstract
Lymphatic absorption in the peritoneal cavity may contribute to ultrafiltration failure in peritoneal dialysis (PD). Lymphatic vessels develop during PD-related peritoneal fibrosis. Connective tissue growth factor (CTGF, also called CCN2) is an important determinant of fibrotic tissue remodeling, but little is known about its possible involvement in lymphangiogenesis. In this study, we investigated the relationship between CTGF and peritoneal lymphangiogenesis. A positive correlation was observed between vascular endothelial growth factor-C (VEGF-C), a major lymphangiogenic growth factor, and the CTGF concentration in human PD effluents. CTGF expression was positively correlated with expression of lymphatic markers and VEGF-C in human peritoneal biopsies. We found a positive correlation between the increase in CTGF and the increase in VEGF-C in cultured human peritoneal mesothelial cells (HPMCs) treated with transforming growth factor-β1 (TGF-β1). The diaphragm is a central player in peritoneal lymphatic absorption. CTGF expression was also correlated with expression of VEGF-C and lymphatics in a rat diaphragmatic fibrosis model induced by chlorhexidine gluconate (CG). Furthermore, CTGF gene deletion reduced VEGF-C expression and peritoneal lymphangiogenesis in the mouse CG model. Inhibition of CTGF also reduced VEGF-C upregulation in HPMCs treated with TGF-β1. Our results suggest a close relationship between CTGF and PD-associated lymphangiogenesis.
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Affiliation(s)
- Hiroshi Kinashi
- Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Japan.,Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Naohiro Toda
- Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ting Sun
- Department of Nephrology and Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tri Q Nguyen
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Yasuhiro Suzuki
- Department of Nephrology and Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takayuki Katsuno
- Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Japan
| | - Hideki Yokoi
- Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Jan Aten
- Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Masashi Mizuno
- Department of Nephrology and Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shoichi Maruyama
- Department of Nephrology and Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Motoko Yanagita
- Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Roel Goldschmeding
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Yasuhiko Ito
- Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Japan.
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15
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Ibrahim MG, Sillem M, Plendl J, Taube ET, Schüring A, Götte M, Chiantera V, Sehouli J, Mechsner S. Arrangement of myofibroblastic and smooth muscle-like cells in superficial peritoneal endometriosis and a possible role of transforming growth factor beta 1 (TGFβ1) in myofibroblastic metaplasia. Arch Gynecol Obstet 2018; 299:489-499. [PMID: 30523440 DOI: 10.1007/s00404-018-4995-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 11/24/2018] [Indexed: 02/06/2023]
Abstract
PURPOSE Superficial peritoneal endometriotic (pEM) lesions are composed of endometrial glands and stroma, in addition to a third component-myofibroblasts and smooth muscles (SM)-like cells. The latter develops secondary to a metaplasia. In this study, we characterised the third component cells in pEM according to differentiation markers in different micro-compartments. Furthermore, a possible effect of TGFβ1 on myofibroblastic metaplasia in endometriotic epithelial cells was studied. METHODS Seventy-six premenopausal patients were included. Peritoneal biopsies were excised from EM patients (n = 23), unaffected peritoneum (peritoneum from EM patients but without EM components, n = 5/23) and non-EM patients (n = 10). All peritoneal biopsies were immunolabeled for ASMA, calponin, collagen I, desmin, TGFß receptor 1 (R1), R2 and R3 in addition to ultrastructure examination by transmission electron microscopy (TEM) (n = 1). TGFß1 level was measured in peritoneal fluid (PF) (EM, n = 19 and non-EM, n = 13) collected during laparoscopy. Furthermore, TGFß1 effect on myofibroblastic metaplasia was studied in vitro. RESULTS At the centre of pEM lesions, calponin immunolabeling outweighs the collagen I while in the periphery the reverse occurs. SM-like cells expressing desmin predominate at the periphery, while ASMA immunolabeling was detectable in all micro-compartments. Both indicate an abundance of myofibroblasts at the centre of pEM lesions and SM-like cells in the periphery. Although activated TGFß1 in PF did not differ between EM and non-EM, it inhibited the cell proliferation of the endometriotic epithelial cells and induced an upregulation in ASMA and collagen IA2 expression as well. CONCLUSION The abundance of the myofibroblasts and SM-like cells points to a myofibroblastic metaplasia in pEM. Both cells are differentially arranged in the different micro-compartments of pEM lesions, with increasing cell maturity towards the periphery of the lesion. Furthermore, TGFß1 may play a role in the myofibroblastic metaplasia of the endometriotic epithelial cells. These findings provide a better insight in the micro-milieu in EM lesions, where most of the disease dynamics occur.
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Affiliation(s)
- Mohamed Gamal Ibrahim
- Clinic for Gynaecology, Charité University of Medicine, Hindenburgdamm 30, 12203, Berlin, Germany
- Department of Gynecology and Obstetrics, UKM Fertility Center, University Hospital of Muenster, Domagkstr. 11, 48149, Münster, Germany
| | - Martin Sillem
- Universitäts-Frauenklinik Homburg/Saar und Praxisklinik am Rosengarten, Augustaanlage 7-11, 68165, Mannheim, Germany
| | - Johanna Plendl
- Department of Veterinary Medicine, Institute of Veterinary Anatomy, Free University of Berlin, Berlin, Germany
| | - Eliane T Taube
- Institute for Pathology, Charité University of Medicine, Charitéplatz 1, 10117, Berlin, Germany
| | - Andreas Schüring
- Department of Gynecology and Obstetrics, UKM Fertility Center, University Hospital of Muenster, Domagkstr. 11, 48149, Münster, Germany
| | - Martin Götte
- Department of Gynecology and Obstetrics, UKM Fertility Center, University Hospital of Muenster, Domagkstr. 11, 48149, Münster, Germany
| | - Vito Chiantera
- Clinic for Gynaecology, Charité University of Medicine, Hindenburgdamm 30, 12203, Berlin, Germany
| | - Jalid Sehouli
- Clinic for Gynaecology, Charité University of Medicine, Hindenburgdamm 30, 12203, Berlin, Germany
| | - Sylvia Mechsner
- Clinic for Gynaecology, Charité University of Medicine, Hindenburgdamm 30, 12203, Berlin, Germany.
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16
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Witowski J, Kamhieh-Milz J, Kawka E, Catar R, Jörres A. IL-17 in Peritoneal Dialysis-Associated Inflammation and Angiogenesis: Conclusions and Perspectives. Front Physiol 2018; 9:1694. [PMID: 30534087 PMCID: PMC6275317 DOI: 10.3389/fphys.2018.01694] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Accepted: 11/09/2018] [Indexed: 12/13/2022] Open
Abstract
Long-term peritoneal dialysis (PD) is associated with peritoneal membrane remodeling. This includes changes in peritoneal vasculature, which may ultimately lead to inadequate solute and water removal and treatment failure. The potential cause of such alterations is chronic inflammation induced by repeated episodes of infectious peritonitis and/or exposure to bioincompatible PD fluids. While these factors may jeopardize the peritoneal membrane integrity, it is not clear why adverse peritoneal remodeling develops only in some PD patients. Increasing evidence points to the differences that occur between patients in response to the same invading microorganism and/or the differences in the course of inflammatory reaction triggered by different species. Such differences may be related to the involvement of different inflammatory mediators. Here, we discuss the potential role of IL-17 in these processes with emphasis on its impact on peritoneal mesothelial cells and peritoneal vascularity.
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Affiliation(s)
- Janusz Witowski
- Department of Pathophysiology, Poznan University of Medical Sciences, Poznań, Poland.,Department of Nephrology, Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Julian Kamhieh-Milz
- Department of Transfusion Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Edyta Kawka
- Department of Pathophysiology, Poznan University of Medical Sciences, Poznań, Poland
| | - Rusan Catar
- Department of Nephrology, Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Berlin Institute of Health, Berlin, Germany
| | - Achim Jörres
- Department of Medicine I, Nephrology, Transplantation, Medical Intensive Care, University of Witten/Herdecke, Cologne-Merheim Medical Center, Cologne, Germany
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17
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Seminal plasma (SP) induces a rapid transforming growth factor beta 1 (TGFβ1)—independent up-regulation of epithelial–mesenchymal transdifferentiation (EMT) and myofibroblastic metaplasia-markers in endometriotic (EM) and endometrial cells. Arch Gynecol Obstet 2018; 299:173-183. [DOI: 10.1007/s00404-018-4965-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2018] [Accepted: 11/08/2018] [Indexed: 10/27/2022]
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18
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Zhang Y, Sun Q, Li X, Ma X, Li Y, Jiao Z, Yang XD. Apigenin suppresses mouse peritoneal fibrosis by down-regulating miR34a expression. Biomed Pharmacother 2018; 106:373-380. [DOI: 10.1016/j.biopha.2018.06.138] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Revised: 06/20/2018] [Accepted: 06/25/2018] [Indexed: 12/18/2022] Open
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19
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González-Mateo GT, Pascual-Antón L, Sandoval P, Aguilera Peralta A, López-Cabrera M. Surgical Techniques for Catheter Placement and 5/6 Nephrectomy in Murine Models of Peritoneal Dialysis. J Vis Exp 2018. [PMID: 30080204 DOI: 10.3791/56746] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
Peritoneal dialysis (PD) is a renal replacement therapy consistent on the administration and posterior recovery of a hyperosmotic fluid in the peritoneal cavity to drain water and toxic metabolites that functionally-insufficient kidneys are not able to eliminate. Unfortunately, this procedure deteriorates the peritoneum. Tissue damage triggers the onset of inflammation to heal the injury. If the injury persists and inflammation becomes chronic, it may lead to fibrosis, which is a common occurrence in many diseases. In PD, chronic inflammation and fibrosis, along with other specific processes related to these ones, lead to ultrafiltration capacity deterioration, which means the failure and subsequent cessation of the technique. Working with human samples provides information about this deterioration but presents technical and ethical limitations to obtain biopsies. Animal models are essential to study this deterioration since they overcome these shortcomings. A chronic mouse infusion model was developed in 2008, which benefits from the wide range of genetically modified mice, opening up the possibility of studying the mechanisms involved. This model employs a customized device designed for mice, consisting of a catheter attached to an access port that is placed subcutaneously at the back of the animal. This procedure avoids continuous puncture of the peritoneum during long-term experiments, reducing infections and inflammation due to injections. Thanks to this model, peritoneal damage induced by chronic PD fluid exposure has been characterized and modulated. This technique allows the infusion of large volumes of fluids and could be used for the study of other diseases in which inoculation of drugs or other substances over extended periods of time is necessary. This article shows the method for the surgical placement of the catheter in mice. Moreover, it explains the procedure for a 5/6 nephrectomy to mimic the state of renal insufficiency present in PD patients.
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Affiliation(s)
- Guadalupe Tirma González-Mateo
- Molecular Biology Research Centre Severo Ochoa, Spanish National Research Council; IdiPAZ Research Institute, La Paz University Hospital;
| | - Lucía Pascual-Antón
- Molecular Biology Research Centre Severo Ochoa, Spanish National Research Council
| | - Pilar Sandoval
- Molecular Biology Research Centre Severo Ochoa, Spanish National Research Council
| | | | - Manuel López-Cabrera
- Molecular Biology Research Centre Severo Ochoa, Spanish National Research Council
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20
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Masola V, Granata S, Bellin G, Gambaro G, Onisto M, Rugiu C, Lupo A, Zaza G. Specific heparanase inhibition reverses glucose-induced mesothelial-to-mesenchymal transition. Nephrol Dial Transplant 2018; 32:1145-1154. [PMID: 28064160 DOI: 10.1093/ndt/gfw403] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Accepted: 10/10/2016] [Indexed: 01/19/2023] Open
Abstract
Background Epithelial-to-mesenchymal transition (EMT) of peritoneal mesothelial cells induced by high glucose (HG) levels is a major biological mechanism leading to myofibroblast accumulation in the omentum of patients on peritoneal dialysis (PD). Heparanase (HPSE), an endoglycosidase that cleaves heparan sulfate chains, is involved in the EMT of several cell lines, and may have a major role in this pro-fibrotic process potentially responsible for the failure of dialysis. Its specific inhibition may therefore plausibly minimize this pathological condition. Methods An in vitro study employing several biomolecular strategies was conducted to assess the role of HPSE in the HG-induced mesothelial EMT process, and to measure the effects of its specific inhibition by SST0001, a N-acetylated glycol-split heparin with a strong anti-HPSE activity. Rat mesothelial cells were grown for 6 days in HG (200 mM) culture medium with or without SST0001. Then EMT markers (VIM, α-SMA, TGF-β) and vascular endothelial growth factor (VEGF) (a factor involved in neoangiogenesis) were measured by real-time PCR and immunofluorescence/western blotting. As a functional analysis, trans-epithelial resistance (TER) and permeability to albumin were also measured in our in vitro model using a Millicell-ERS ohmmeter and a spectrophotometer, respectively. Results Our results showed that 200 mM of glucose induced a significant gene and protein up-regulation of VEGF and all EMT markers after 6 days of culture. Intriguingly, adding SST0001 on day 3 reversed these biological and cellular effects. HPSE inhibition also restored the normal TER and permeability lost during the HG treatment. Conclusion Taken together, our data confirm that HG can induce EMT of mesothelial cells, and that HPSE plays a central part in this process. Our findings also suggest that pharmacological HPSE inhibition could prove a valuable therapeutic tool for minimizing fibrosis and avoiding a rapid decline in the efficacy of dialysis in patients on PD, though clinical studies and/or trials would be needed to confirm the clinical utility of this treatment.
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Affiliation(s)
- Valentina Masola
- Renal Unit, Department of Medicine, Verona University Hospital, Verona, Italy
| | - Simona Granata
- Renal Unit, Department of Medicine, Verona University Hospital, Verona, Italy
| | - Gloria Bellin
- Renal Unit, Department of Medicine, Verona University Hospital, Verona, Italy
| | - Giovanni Gambaro
- Nephrology and Dialysis Division, Columbus-Gemelli Hospital, Catholic University School of Medicine, Rome, Italy
| | - Maurizio Onisto
- Department of Biomedical Sciences, University of Padova, Padova, Italy
| | - Carlo Rugiu
- Renal Unit, Department of Medicine, Verona University Hospital, Verona, Italy
| | - Antonio Lupo
- Renal Unit, Department of Medicine, Verona University Hospital, Verona, Italy
| | - Gianluigi Zaza
- Renal Unit, Department of Medicine, Verona University Hospital, Verona, Italy
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21
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Wilson RB. Hypoxia, cytokines and stromal recruitment: parallels between pathophysiology of encapsulating peritoneal sclerosis, endometriosis and peritoneal metastasis. Pleura Peritoneum 2018; 3:20180103. [PMID: 30911653 PMCID: PMC6405013 DOI: 10.1515/pp-2018-0103] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Accepted: 03/01/2018] [Indexed: 02/06/2023] Open
Abstract
Peritoneal response to various kinds of injury involves loss of peritoneal mesothelial cells (PMC), danger signalling, epithelial-mesenchymal transition and mesothelial-mesenchymal transition (MMT). Encapsulating peritoneal sclerosis (EPS), endometriosis (EM) and peritoneal metastasis (PM) are all characterized by hypoxia and formation of a vascularized connective tissue stroma mediated by vascular endothelial growth factor (VEGF). Transforming growth factor-β1 (TGF-β1) is constitutively expressed by the PMC and plays a major role in the maintenance of a transformed, inflammatory micro-environment in PM, but also in EPS and EM. Persistently high levels of TGF-β1 or stimulation by inflammatory cytokines (interleukin-6 (IL-6)) induce peritoneal MMT, adhesion formation and fibrosis. TGF-β1 enhances hypoxia inducible factor-1α expression, which drives cell growth, extracellular matrix production and cell migration. Disruption of the peritoneal glycocalyx and exposure of the basement membrane release low molecular weight hyaluronan, which initiates a cascade of pro-inflammatory mediators, including peritoneal cytokines (TNF-α, IL-1, IL-6, prostaglandins), growth factors (TGF-α, TGF-β, platelet-derived growth factor, VEGF, epidermal growth factor) and the fibrin/coagulation cascade (thrombin, Tissue factor, plasminogen activator inhibitor [PAI]-1/2). Chronic inflammation and cellular transformation are mediated by damage-associated molecular patterns, pattern recognition receptors, AGE-RAGE, extracellular lactate, pro-inflammatory cytokines, reactive oxygen species, increased glycolysis, metabolomic reprogramming and cancer-associated fibroblasts. The pathogenesis of EPS, EM and PM shows similarities to the cellular transformation and stromal recruitment of wound healing.
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Affiliation(s)
- Robert Beaumont Wilson
- Upper GI Surgery Department, Liverpool Hospital, Elizabeth St, Liverpool, 2170, NSW, Australia
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22
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Kariya T, Nishimura H, Mizuno M, Suzuki Y, Matsukawa Y, Sakata F, Maruyama S, Takei Y, Ito Y. TGF-β1-VEGF-A pathway induces neoangiogenesis with peritoneal fibrosis in patients undergoing peritoneal dialysis. Am J Physiol Renal Physiol 2018; 314:F167-F180. [DOI: 10.1152/ajprenal.00052.2017] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
The characteristic features of chronic peritoneal injury with peritoneal dialysis (PD) are submesothelial fibrosis and neoangiogenesis. Transforming growth factor (TGF)β and vascular endothelial growth factor (VEGF)-A are the main mediators of fibrosis and neoangiogenesis, respectively; however, the effect of the interaction between them on the peritoneum is not well known. In this study, we investigated the relationship between TGF-β1 and VEGF-A in inducing peritoneal fibrosis by use of human tissues and dialysate, cultured cells, and animal models. The VEGF-A concentration correlated with the dialysate-to-plasma ratio of creatinine (D/P Cr) ( P < 0.001) and TGF-β1 ( P < 0.001) in human PD effluent. VEGF-A mRNA levels increased significantly in the peritoneal tissues of human ultrafiltration failure (UFF) patients and correlated with number of vessels ( P < 0.01) and peritoneal thickness ( P < 0.001). TGF-β1 increased VEGF-A production in human mesothelial cell lines and fibroblast cell lines, and TGF-β1-induced VEGF-A was suppressed by TGF-β receptor I (TGFβR-I) inhibitor. Incremental peak values of VEGF-A mRNA stimulated by TGF-β1 in human cultured mesothelial cells derived from PD patients with a range of peritoneal membrane functions correlated with D/P Cr ( P < 0.05). To evaluate the regulatory mechanisms of VEGF-A and neoangiogenesis in vivo, we administered TGFβR-I inhibitor intraperitoneally in a rat chlorhexidine-induced peritoneal injury (CG) model. TGFβR-I inhibitor administration in the CG model decreased peritoneal thickness ( P < 0.001), the number of vessels ( P < 0.001), and VEGF-A levels ( P < 0.05). These results suggest that neoangiogenesis is associated with fibrosis through the TGF-β1-VEGF-A pathway in mesothelial cells and fibroblasts. These findings are important when considering the strategy for management of UFF in PD patients.
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Affiliation(s)
- Tetsuyoshi Kariya
- Department of Nephrology and Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hayato Nishimura
- Department of Nephrology and Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Futatsuya Hospital, Ishikawa, Japan
| | - Masashi Mizuno
- Department of Nephrology and Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasuhiro Suzuki
- Department of Nephrology and Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshihisa Matsukawa
- Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Fumiko Sakata
- Department of Nephrology and Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shoichi Maruyama
- Department of Nephrology and Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshifumi Takei
- Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Medical Biochemistry, School of Pharmacy, Aichi Gakuin University, Nagoya, Japan
| | - Yasuhiko Ito
- Department of Nephrology and Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Nephrology and Rheumatology, Aichi Medical University School of Medicine, Aichi, Japan
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23
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Wang Q, Yang X, Xu Y, Shen Z, Cheng H, Cheng F, Liu X, Wang R. RhoA/Rho-kinase triggers epithelial-mesenchymal transition in mesothelial cells and contributes to the pathogenesis of dialysis-related peritoneal fibrosis. Oncotarget 2018; 9:14397-14412. [PMID: 29581852 PMCID: PMC5865678 DOI: 10.18632/oncotarget.24208] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Accepted: 12/05/2017] [Indexed: 12/22/2022] Open
Abstract
Peritoneal fibrosis (PF) with associated peritoneal dysfunction is almost invariably observed in long-term peritoneal dialysis (PD) patients. Advanced glycation end products (AGEs) are pro-oxidant compounds produced in excess during the metabolism of glucose and are present in high levels in standard PD solutions. The GTPase RhoA has been implicated in PF, but its specific role remains poorly understood. Here, we studied the effects of RhoA/Rho-kinase signaling in AGEs-induced epithelial-mesenchymal transition (EMT) in human peritoneal mesothelial cells (HPMCs), and evaluated morphological and molecular changes in a rat model of PD-related PF. Activation of RhoA/Rho-kinase and activating protein-1 (AP-1) was assessed in HPMCs using pull-down and electrophoretic mobility shift assays, respectively, while expression of transforming growth factor-β, fibronectin, α-smooth muscle actin, vimentin, N-cadherin, and E-cadherin expression was assessed using immunohistochemistry and western blot. AGEs exposure activated Rho/Rho-kinase in HPMCs and upregulated EMT-related genes via AP-1. These changes were prevented by the Rho-kinase inhibitors fasudil and Y-27632, and by the AP-1 inhibitor curcumin. Importantly, fasudil normalized histopathological and molecular alterations and preserved peritoneal function in rats. These data support the therapeutic potential of Rho-kinase inhibitors in PD-related PF.
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Affiliation(s)
- Qinglian Wang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Xiaowei Yang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Ying Xu
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Zhenwei Shen
- Department of Biostatistics, School of Public Health, Shandong University, Jinan, China
| | - Hongxia Cheng
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Fajuan Cheng
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Xiang Liu
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Rong Wang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
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24
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Herrick SE, Mutsaers SE. The Potential of Mesothelial Cells in Tissue Engineering and Regenerative Medicine Applications. Int J Artif Organs 2018; 30:527-40. [PMID: 17628854 DOI: 10.1177/039139880703000611] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Injury to the serosa through injurious agents such as radiation, surgery, infection and disease results in the loss of the protective surface mesothelium and often leads to fibrous adhesion formation. Mechanisms that increase the rate of mesothialisation are therefore actively being investigated in order to reduce the formation of adhesions. These include intraperitoneal delivery of cultured mesothelial cells as well as administration of factors that are known to increase mesothelial proliferation and migration. An exciting alternative that has only recently received attention, is the possible role of mesothelial progenitor cells in the repair and regeneration of denuded serosal areas. Accumulating evidence suggests that such a population exists and under certain conditions is able to form a number of defined cell types indicating a degree of plasticity. Such properties may explain the extensive use of mesothelial cells in various tissue engineering applications including the development of vascular conduits and peripheral nerve replacements. It is likely that with the rapid explosion in the fields of tissue engineering and regenerative medicine, a greater understanding of the potential of mesothelial progenitor cells to repair, replace and possibly regenerate damaged or defective tissue will be uncovered.
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Affiliation(s)
- S E Herrick
- School of Medicine, Faculty of Medical and Human Sciences, University of Manchester, Oxford Road, Manchester, UK.
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25
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Igarashi Y, Hoshino T, Ookawara S, Ishibashi K, Morishita Y. Nano-sized carriers in gene therapy for peritoneal fibrosis in vivo. NANO REVIEWS & EXPERIMENTS 2017; 8:1331100. [PMID: 30410706 PMCID: PMC6167028 DOI: 10.1080/20022727.2017.1331100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Accepted: 05/11/2017] [Indexed: 11/07/2022]
Abstract
Peritoneal fibrosis is a crucial complication in patients receiving peritoneal dialysis. It is a major pathological feature of peritoneal membrane failure, which leads to withdrawal of peritoneal dialysis. No specific therapy has yet been established for the treatment of peritoneal fibrosis. However, gene therapy may be a viable option, and various nano-sized carriers, including viral and non-viral vectors, have been shown to enhance the delivery and efficacy of gene therapy for peritoneal fibrosis in vivo. This review focuses on the use of nano-sized carriers in gene therapy of peritoneal fibrosis in vivo.
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Affiliation(s)
- Yusuke Igarashi
- Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan
| | - Taro Hoshino
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Susumu Ookawara
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Kenichi Ishibashi
- Department of Medical Physiology, Meiji Pharmaceutical University, Tokyo, Japan
| | - Yoshiyuki Morishita
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
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26
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Yang CY, Chau YP, Chen A, Lee OKS, Tarng DC, Yang AH. Targeting cannabinoid signaling for peritoneal dialysis-induced oxidative stress and fibrosis. World J Nephrol 2017; 6:111-118. [PMID: 28540200 PMCID: PMC5424432 DOI: 10.5527/wjn.v6.i3.111] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 01/20/2017] [Accepted: 02/20/2017] [Indexed: 02/06/2023] Open
Abstract
Long-term exposure to bioincompatible peritoneal dialysis (PD) solutions frequently results in peritoneal fibrosis and ultrafiltration failure, which limits the life-long use of and leads to the cessation of PD therapy. Therefore, it is important to elucidate the pathogenesis of peritoneal fibrosis in order to design therapeutic strategies to prevent its occurrence. Peritoneal fibrosis is associated with a chronic inflammatory status as well as an elevated oxidative stress (OS) status. Beyond uremia per se, OS also results from chronic exposure to high glucose load, glucose degradation products, advanced glycation end products, and hypertonic stress. Therapy targeting the cannabinoid (CB) signaling pathway has been reported in several chronic inflammatory diseases with elevated OS. We recently reported that the intra-peritoneal administration of CB receptor ligands, including CB1 receptor antagonists and CB2 receptor agonists, ameliorated dialysis-related peritoneal fibrosis. As targeting the CB signaling pathway has been reported to be beneficial in attenuating the processes of several chronic inflammatory diseases, we reviewed the interaction among the cannabinoid system, inflammation, and OS, through which clinicians ultimately aim to prolong the peritoneal survival of PD patients.
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Mottaghitalab F, Rastegari A, Farokhi M, Dinarvand R, Hosseinkhani H, Ou KL, Pack DW, Mao C, Dinarvand M, Fatahi Y, Atyabi F. Prospects of siRNA applications in regenerative medicine. Int J Pharm 2017; 524:312-329. [PMID: 28385649 DOI: 10.1016/j.ijpharm.2017.03.092] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 03/14/2017] [Accepted: 03/31/2017] [Indexed: 12/18/2022]
Abstract
Small interfering RNA (siRNA) has established its reputation in the field of tissue engineering owing to its ability to silence the proteins that inhibit tissue regeneration. siRNA is capable of regulating cellular behavior during tissue regeneration processes. The concept of using siRNA technology in regenerative medicine derived from its ability to inhibit the expression of target genes involved in defective tissues and the possibility to induce the expression of tissue-inductive factors that improve the tissue regeneration process. To date, siRNA has been used as a suppressive biomolecule in different tissues, such as nervous tissue, bone, cartilage, heart, kidney, and liver. Moreover, various delivery systems have been applied in order to deliver siRNA to the target tissues. This review will provide an in-depth discussion on the development of siRNA and their delivery systems and mechanisms of action in different tissues.
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Affiliation(s)
- Fatemeh Mottaghitalab
- Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Rastegari
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehdi Farokhi
- National Cell Bank of Iran, Pasteur Institute of Iran, Tehran, Iran
| | - Rassoul Dinarvand
- Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Hosseinkhani
- Innovation Center for Advanced Technology, Matrix, Inc., New York, NY 10029, USA
| | - Keng-Liang Ou
- Research Center for Biomedical Devices and Prototyping Production, Research Center for Biomedical Implants and Microsurgery Devices, Taipei Medical University, Taipei, Taiwan
| | - Daniel W Pack
- Department of Chemical & Materials Engineering and Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, United States
| | - Chuanbin Mao
- Department of Chemistry & Biochemistry, Stephenson Life Science Research Center, University of Oklahoma, 101 Stephenson Parkway, Norman, OK 73019, United States; School of Materials Science and Engineering, Zhejiang University, Hangzhou, Zhejiang 310027, China
| | - Meshkat Dinarvand
- Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Yousef Fatahi
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Atyabi
- Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
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Oh SH, Kang JG, Lee JH. Co-micellized Pluronic mixture with thermo-sensitivity and residence stability as an injectable tissue adhesion barrier hydrogel. J Biomed Mater Res B Appl Biomater 2016; 106:172-182. [DOI: 10.1002/jbm.b.33824] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 10/20/2016] [Accepted: 11/16/2016] [Indexed: 12/20/2022]
Affiliation(s)
- Se Heang Oh
- Department of Nanobiomedical Science; Dankook University; Cheonan 31116 Republic of Korea
| | - Jun Goo Kang
- Department of Advanced Materials; Hannam University; Daejeon 34054 Republic of Korea
| | - Jin Ho Lee
- Department of Advanced Materials; Hannam University; Daejeon 34054 Republic of Korea
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Mori Y, Kakuta T, Miyakogawa T, Takekoshi S, Yuzawa H, Kobayashi H, Kawakami A, Miyata T, Fukagawa M. Effect of Scavenging Circulating Reactive Carbonyls by Oral Pyridoxamine in Uremic Rats on Peritoneal Dialysis. Ther Apher Dial 2016; 20:645-654. [PMID: 27620210 DOI: 10.1111/1744-9987.12446] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Revised: 04/06/2016] [Accepted: 04/12/2016] [Indexed: 11/30/2022]
Abstract
Pyridoxamine, a reactive carbonyl (RCO) scavenger, can ameliorate peritoneal deterioration in uremic peritoneal dialysis (PD) rats when given via dialysate. We examined the effects of scavenging circulating RCOs by oral pyridoxamine. Rats underwent nephrectomy and 3 weeks of twice daily PD either alone or with once daily oral pyridoxamine. PD solution was supplemented with methylglyoxal, a major glucose-derived RCO, to quench intraperitoneal pyridoxamine. Oral pyridoxamine achieved comparable blood and dialysate pyridoxamine concentrations, suppressed pentosidine accumulation in the blood but not in the mesenterium or dialysate, and reduced the increases in small solute transport and mesenteric vessel densities, with no effects on submesothelial matrix layer thickening or serum creatinine. Thus, reducing circulating RCOs by giving oral pyridoxamine with PD provides limited peritoneal protection. However, orally given pyridoxamine efficiently reaches the peritoneal cavity and would eliminate intraperitoneal RCOs. Oral pyridoxamine is more clinically favorable and may be as protective as intraperitoneal administration.
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Affiliation(s)
- Yoshitaka Mori
- Department of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara, Japan.,Unit of Translational Medicine, Department of Endocrinology and Metabolism, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Takatoshi Kakuta
- Department of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara, Japan.,Department of Nephrology, Endocrinology and Metabolism, Tokai University Hachioji Hospital, Hachioji, Tokyo, Japan
| | - Takayo Miyakogawa
- Department of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara, Japan
| | - Susumu Takekoshi
- Division of Basic Molecular Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Hiroko Yuzawa
- Department of Neurology, Tokai University School of Medicine, Isehara, Japan
| | - Hiroyuki Kobayashi
- Department of Clinical Pharmacology, Tokai University School of Medicine, Isehara, Japan
| | - Atsushi Kawakami
- Unit of Translational Medicine, Department of Endocrinology and Metabolism, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Toshio Miyata
- United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Masafumi Fukagawa
- Department of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara, Japan
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Diabetes and exposure to peritoneal dialysis solutions alter tight junction proteins and glucose transporters of rat peritoneal mesothelial cells. Life Sci 2016; 161:78-89. [DOI: 10.1016/j.lfs.2016.07.018] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Revised: 07/25/2016] [Accepted: 07/30/2016] [Indexed: 01/08/2023]
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Kitamura M, Nishino T, Obata Y, Oka S, Abe S, Muta K, Ozono Y, Koji T, Kohno S. The kampo medicine Daikenchuto inhibits peritoneal fibrosis in mice. Biol Pharm Bull 2015; 38:193-200. [PMID: 25747978 DOI: 10.1248/bpb.b14-00469] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Long-term peritoneal dialysis therapy causes inflammation and histological changes in the peritoneal membrane. Inflammation generally activates fibroblasts and results in fibroblast-myofibroblast differentiation. Heat-shock protein 47 (HSP 47), a collagen-specific molecular chaperone, is localized in myofibroblasts and is involved in the progression of peritoneal fibrosis. Daikenchuto (DKT), a Kampo medicine, is used to prevent postoperative colon adhesion. It inhibits inflammation and HSP 47 expression in the gastrointestinal tract. We examined the effect of DKT on chlorhexidine gluconate (CG)-induced peritoneal fibrosis in mice injected with 0.1% CG dissolved in 15% ethanol. DKT was dissolved in the drinking water. Histological changes were assessed using Masson trichrome staining. Cells expressing α-smooth muscle actin (α-SMA), HSP 47, phospho-Smad 2/3, F4/80, and monocyte chemotactic protein-1 were examined immunohistochemically. Compared with the control group, the peritoneal tissues of the CG group were markedly thickened, and the number of cells expressing α-SMA, HSP 47, phospho-Smad 2/3, F4/80, and monocyte chemotactic protein-1 was significantly increased. However, these changes were inhibited in the DKT-treated group. These results indicate that DKT can prevent peritoneal fibrosis by inhibiting inflammation and HSP 47 expression.
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Affiliation(s)
- Mineaki Kitamura
- Second Department of Internal Medicine, Nagasaki University School of Medicine
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Effluent Tenascin-C Levels Reflect Peritoneal Deterioration in Peritoneal Dialysis: MAJOR IN PD Study. BIOMED RESEARCH INTERNATIONAL 2015; 2015:241098. [PMID: 26770971 PMCID: PMC4684852 DOI: 10.1155/2015/241098] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Revised: 09/04/2015] [Accepted: 10/29/2015] [Indexed: 01/03/2023]
Abstract
Peritoneal deterioration causing structural changes and functional decline is a major complication of peritoneal dialysis (PD). The aim of this study was to explore effluent biomarkers reflecting peritoneal deterioration. In an animal study, rats were intraperitoneally administered with PD fluids adding 20 mM methylglyoxal (MGO) or 20 mM formaldehyde (FA) every day for 21 days. In the MGO-treated rats, tenascin-C (TN-C) levels in the peritoneal effluents were remarkably high and a cluster of TN-C-positive mesothelial cells with epithelial-to-mesenchymal transition- (EMT-) like change excessively proliferated at the peritoneal surface, but not in the FA-treated rats. Effluent matrix metalloproteinase-2 (MMP-2) levels increased in both the MGO- and FA-treated rats. In a clinical study at 18 centers between 2006 and 2013, effluent TN-C and MMP-2 levels were quantified in 182 PD patients with end-stage renal disease. Peritoneal function was estimated using the peritoneal equilibration test (PET). From the PET results, the D/P Cr ratio was correlated with effluent levels of TN-C (ρ = 0.57, p < 0.001) and MMP-2 (ρ = 0.73, p < 0.001). We suggest that TN-C in the effluents may be a diagnostic marker for peritoneal deterioration with EMT-like change in mesothelial cells in PD.
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Isoyama N, Machowska A, Qureshi AR, Yamamoto T, Anderstam B, Heimburger O, Barany P, Stenvinkel P, Lindholm B. Elevated Circulating S100A12 Associates with Vascular Disease and Worse Clinical Outcome in Peritoneal Dialysis Patients. Perit Dial Int 2015; 36:269-76. [PMID: 26493750 DOI: 10.3747/pdi.2014.00121] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2014] [Accepted: 03/01/2015] [Indexed: 11/15/2022] Open
Abstract
UNLABELLED ♦ BACKGROUND The pro-inflammatory receptor of advanced glycation end-products (RAGE)-ligand S100A12 is thought to promote, whereas anti-inflammatory soluble RAGE (sRAGE) may protect against, vascular disease. We evaluated circulating S100A12 and sRAGE in relation to vascular disease, inflammation, nutritional status, and mortality risk in peritoneal dialysis (PD) patients. ♦ METHODS Plasma S100A12 and sRAGE, biomarkers of inflammation, nutritional status, and comorbidities were analyzed in 82 prevalent PD patients (median age 65 years; 70% men; median vintage 12 months) and, for comparative analysis, also in 190 hemodialysis (HD) patients and 50 control subjects. Associations between mortality risk and concentrations of S100A12 and sRAGE were assessed in PD and HD patients after a mean follow-up period of 31 and 29 months respectively using a competing risk Cox regression model. ♦ RESULTS In PD patients, median S100A12, sRAGE and S100A12/sRAGE were markedly higher than in controls, and S100A12 was 1.9 times higher and median sRAGE 14% lower compared with HD patients. In PD patients, S100A12 associated with C-reactive protein (ρ = 0.46; p < 0.001) and interleukin-6 (ρ = 0.38; p < 0.001), and, negatively, with s-albumin (ρ = -0.27; p < 0.05) whereas sRAGE associated negatively with body mass index (ρ = -0.37; p < 0.001), fat body mass index (ρ = -0.34; p < 0.001), and lean body mass index (ρ = -0.36; p < 0.001). Peripheral vascular disease or cerebrovascular disease (PCVD) was present in 28% of PD patients and, in multivariate analysis, associated mainly with high S100A12 (odds ratio [OR] 3.52, p = 0.04). In both PD and HD patients, the highest versus other tertiles of S100A12 associated with increased mortality. In contrast, sRAGE did not associate with PCVD or mortality in PD and HD patients. ♦ CONCLUSIONS Plasma S100A12 and sRAGE are markedly elevated in PD patients. Soluble RAGE was inversely related to body mass indices while S100A12 associated with increased inflammation, PCVD, and mortality, suggesting that S100A12 may identify PD patients at high risk for vascular disease and increased mortality.
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Affiliation(s)
- Naohito Isoyama
- Divisions of Renal Medicine and Baxter Novum, Karolinska Institutet, Stockholm, Sweden Department of Urology, Yamaguchi University, Ube, Yamaguchi, Japan
| | - Anna Machowska
- Divisions of Renal Medicine and Baxter Novum, Karolinska Institutet, Stockholm, Sweden Baxter Healthcare Corporation Europe, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Abdul Rashid Qureshi
- Divisions of Renal Medicine and Baxter Novum, Karolinska Institutet, Stockholm, Sweden
| | - Tae Yamamoto
- Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Björn Anderstam
- Divisions of Renal Medicine and Baxter Novum, Karolinska Institutet, Stockholm, Sweden
| | - Olof Heimburger
- Divisions of Renal Medicine and Baxter Novum, Karolinska Institutet, Stockholm, Sweden
| | - Peter Barany
- Divisions of Renal Medicine and Baxter Novum, Karolinska Institutet, Stockholm, Sweden
| | - Peter Stenvinkel
- Divisions of Renal Medicine and Baxter Novum, Karolinska Institutet, Stockholm, Sweden
| | - Bengt Lindholm
- Divisions of Renal Medicine and Baxter Novum, Karolinska Institutet, Stockholm, Sweden
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Mutsaers HAM, Stribos EGD, Glorieux G, Vanholder R, Olinga P. Chronic Kidney Disease and Fibrosis: The Role of Uremic Retention Solutes. Front Med (Lausanne) 2015; 2:60. [PMID: 26380262 PMCID: PMC4553389 DOI: 10.3389/fmed.2015.00060] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Accepted: 08/17/2015] [Indexed: 12/20/2022] Open
Abstract
Chronic kidney disease (CKD) is a major global health concern, and the uremic state is highly associated with fibrogenesis in several organs and tissues. Fibrosis is characterized by excessive production and deposition of extracellular matrix proteins with a detrimental impact on organ function. Another key feature of CKD is the retention and subsequent accumulation of solutes that are normally cleared by the healthy kidney. Several of these uremic retention solutes, including indoxyl sulfate and p-cresyl sulfate, have been suggested to be CKD-specific triggers for the development and perpetuation of fibrosis. The purpose of this brief review is to gather and discuss the current body of evidence linking uremic retention solutes to the fibrotic response during CKD, with a special emphasis on the pathophysiological mechanisms in the kidney.
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Affiliation(s)
- Henricus A M Mutsaers
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen , Groningen , Netherlands
| | - Elisabeth G D Stribos
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen , Groningen , Netherlands ; Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen , Groningen , Netherlands
| | - Griet Glorieux
- Renal Division, Department of Internal Medicine, Ghent University Hospital , Ghent , Belgium
| | - Raymond Vanholder
- Renal Division, Department of Internal Medicine, Ghent University Hospital , Ghent , Belgium
| | - Peter Olinga
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen , Groningen , Netherlands
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Mutsaers SE, Birnie K, Lansley S, Herrick SE, Lim CB, Prêle CM. Mesothelial cells in tissue repair and fibrosis. Front Pharmacol 2015; 6:113. [PMID: 26106328 PMCID: PMC4460327 DOI: 10.3389/fphar.2015.00113] [Citation(s) in RCA: 144] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Accepted: 05/12/2015] [Indexed: 12/21/2022] Open
Abstract
Mesothelial cells are fundamental to the maintenance of serosal integrity and homeostasis and play a critical role in normal serosal repair following injury. However, when normal repair mechanisms breakdown, mesothelial cells take on a profibrotic role, secreting inflammatory, and profibrotic mediators, differentiating and migrating into the injured tissues where they contribute to fibrogenesis. The development of new molecular and cell tracking techniques has made it possible to examine the origin of fibrotic cells within damaged tissues and to elucidate the roles they play in inflammation and fibrosis. In addition to secreting proinflammatory mediators and contributing to both coagulation and fibrinolysis, mesothelial cells undergo mesothelial-to-mesenchymal transition, a process analogous to epithelial-to-mesenchymal transition, and become fibrogenic cells. Fibrogenic mesothelial cells have now been identified in tissues where they have not previously been thought to occur, such as within the parenchyma of the fibrotic lung. These findings show a direct role for mesothelial cells in fibrogenesis and open therapeutic strategies to prevent or reverse the fibrotic process.
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Affiliation(s)
- Steven E Mutsaers
- Centre for Cell Therapy and Regenerative Medicine, School of Medicine and Pharmacology, University of Western Australia and Harry Perkins Institute of Medical Research , Nedlands, WA, Australia ; Institute for Respiratory Health, Centre for Asthma, Allergy and Respiratory Research, School of Medicine and Pharmacology, University of Western Australia , Nedlands, WA, Australia
| | - Kimberly Birnie
- Institute for Respiratory Health, Centre for Asthma, Allergy and Respiratory Research, School of Medicine and Pharmacology, University of Western Australia , Nedlands, WA, Australia
| | - Sally Lansley
- Institute for Respiratory Health, Centre for Asthma, Allergy and Respiratory Research, School of Medicine and Pharmacology, University of Western Australia , Nedlands, WA, Australia
| | - Sarah E Herrick
- Institute of Inflammation and Repair, Faculty of Medical and Human Sciences and Manchester Academic Health Science Centre, University of Manchester , Manchester, UK
| | - Chuan-Bian Lim
- Centre for Cell Therapy and Regenerative Medicine, School of Medicine and Pharmacology, University of Western Australia and Harry Perkins Institute of Medical Research , Nedlands, WA, Australia ; Institute for Respiratory Health, Centre for Asthma, Allergy and Respiratory Research, School of Medicine and Pharmacology, University of Western Australia , Nedlands, WA, Australia
| | - Cecilia M Prêle
- Centre for Cell Therapy and Regenerative Medicine, School of Medicine and Pharmacology, University of Western Australia and Harry Perkins Institute of Medical Research , Nedlands, WA, Australia ; Institute for Respiratory Health, Centre for Asthma, Allergy and Respiratory Research, School of Medicine and Pharmacology, University of Western Australia , Nedlands, WA, Australia
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Qin F, Ma Y, Li X, Wang X, Wei Y, Hou C, Lin S, Hou L, Wang C. Efficacy and mechanism of tanshinone IIA liquid nanoparticles in preventing experimental postoperative peritoneal adhesions in vivo and in vitro. Int J Nanomedicine 2015; 10:3699-716. [PMID: 26056449 PMCID: PMC4445949 DOI: 10.2147/ijn.s81650] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Up to 90% of patients develop adhesion following laparotomy. Upregulating fibrinolysis within the peritoneum reduces adhesions. Tanshinone IIA (Tan IIA) promotes fibrinolysis in hepatic fibrosis and the cardiovascular system and may play a role in preventing adhesions. We report preparation and characterization of liquid nanoparticles of Tan IIA for intravenous administration and investigate its feasibility in clinical practice. Tan IIA liquid nanoparticles (Tan IIA-NPs) were prepared using the emulsion/solvent evaporation method. Adhesions were induced in Sprague–Dawley rats by injuring the parietal peritoneum and cecum, followed by intravenous administration of various Tan IIA-NP dosages. The adhesion scores for each group were collected 7 days after the initial laparotomy. The activity of tissue-type plasminogen activator (tPA) was measured from the peritoneal lavage fluid. The messenger RNA and protein expression levels of plasminogen activator inhibitor-1 (PAI-1) were measured by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. TGF-β1 and collagen I expressions were measured immunohistochemically in the ischemic tissues. The effects of Tan IIA-NPs and free-Tan IIA on tPA and PAI-1 were measured in vitro in TGF-β1-induced HMrSV5 cells. Tan IIA-NPs exhibited small particle size, high encapsulation efficiency, good stability for storage, and safety for intravenous administration. Tan IIA-NPs were effective in preventing adhesion. Tan IIA-NPs increased tPA activity in peritoneal lavage fluid, and tPA mRNA and protein expression, and decreased PAI-1 mRNA and protein expression in the ischemic tissues. Moreover, Tan IIA-NPs decreased TGF-β1 and collagen I expressions in the ischemic tissues. Tan IIA-NPs administered via tail veins upregulated fibrinolysis in the peritoneum. In vitro studies showed that these effects may be mediated by the TGF-β signal pathway.
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Affiliation(s)
- Fei Qin
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Yun Ma
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Xiao Li
- Department of Pharmacy, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, People's Republic of China
| | - Xian Wang
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Yuanyi Wei
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Chuqi Hou
- Department of Pharmacology, Southern Medical University, Guangzhou, People's Republic of China
| | - Si Lin
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Lianbing Hou
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Chengxi Wang
- Department of Pharmacology, Guangdong Pharmaceutical University, Guangzhou, People's Republic of China
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Moinuddin Z, Summers A, Van Dellen D, Augustine T, Herrick SE. Encapsulating peritoneal sclerosis-a rare but devastating peritoneal disease. Front Physiol 2015; 5:470. [PMID: 25601836 PMCID: PMC4283512 DOI: 10.3389/fphys.2014.00470] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Accepted: 11/16/2014] [Indexed: 01/08/2023] Open
Abstract
Encapsulating peritoneal sclerosis (EPS) is a devastating but, fortunately, rare complication of long-term peritoneal dialysis. The disease is associated with extensive thickening and fibrosis of the peritoneum resulting in the formation of a fibrous cocoon encapsulating the bowel leading to intestinal obstruction. The incidence of EPS ranges between 0.7 and 3.3% and increases with duration of peritoneal dialysis therapy. Dialysis fluid is hyperosmotic, hyperglycemic, and acidic causing chronic injury and inflammation in the peritoneum with loss of mesothelium and extensive tissue fibrosis. The pathogenesis of EPS, however, still remains uncertain, although a widely accepted hypothesis is the "two-hit theory," where, the first hit is chronic peritoneal membrane injury from long standing peritoneal dialysis followed by a second hit such as an episode of peritonitis, genetic predisposition and/or acute cessation of peritoneal dialysis, leading to EPS. Recently, EPS has been reported in patients shortly after transplantation suggesting that this procedure may also act as a possible second insult. The process of epithelial-mesenchymal transition of mesothelial cells is proposed to play a central role in the development of peritoneal sclerosis, a common characteristic of patients on dialysis, however, its importance in EPS is less clear. There is no established treatment for EPS although evidence from small case studies suggests that corticosteroids and tamoxifen may be beneficial. Nutritional support is essential and surgical intervention (peritonectomy and enterolysis) is recommended in later stages to relieve bowel obstruction.
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Affiliation(s)
- Zia Moinuddin
- Department of Transplantation, Manchester Royal Infirmary Manchester, UK ; Faculty of Medical and Human Sciences, Institute of Inflammation and Repair, University of Manchester, Manchester Academic Health Science Centre Manchester, UK
| | - Angela Summers
- Department of Transplantation, Manchester Royal Infirmary Manchester, UK
| | - David Van Dellen
- Department of Transplantation, Manchester Royal Infirmary Manchester, UK
| | - Titus Augustine
- Department of Transplantation, Manchester Royal Infirmary Manchester, UK
| | - Sarah E Herrick
- Faculty of Medical and Human Sciences, Institute of Inflammation and Repair, University of Manchester, Manchester Academic Health Science Centre Manchester, UK
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Onishi A, Akimoto T, Morishita Y, Hirahara I, Inoue M, Kusano E, Nagata D. Peritoneal fibrosis induced by intraperitoneal methylglyoxal injection: the role of concurrent renal dysfunction. Am J Nephrol 2014; 40:381-90. [PMID: 25358632 DOI: 10.1159/000368424] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Accepted: 09/16/2014] [Indexed: 01/29/2023]
Abstract
BACKGROUND Peritoneal fibrosis (PF) is a serious pathophysiology of peritoneal dialysis (PD). An ongoing focus of research is the potential fibrogenic nature of methylglyoxal (MGO) in conventional PD fluid (PDF). The aim of the current study was to explore the effects of the uremic milieu on the promotion of PF by MGO using rats with adenine-induced renal failure (RF). METHODS Adenine-treated Sprague-Dawley rats were randomly assigned to receive continuous peritoneal injections of PDF with or without MGO for three weeks or were left untreated for the same duration. Rats without RF were also assigned to three groups. The peritoneal histology and expression levels of type I collagen, transforming growth factor-β1 (TGF-β1), α-smooth muscle actin (αSMA), Snail, matrix metalloproteinase-2 (MMP-2), advanced glycation end-products (AGEs) and the receptor for AGE (RAGE) were then analyzed. RESULTS Peritoneal treatment with 5 mM MGO accelerated the fibrous peritoneal thickening progression promoted by exposure to standard PDF in the rats with RF, but not in the rats with a normal renal function. Treatment with MGO significantly augmented the proliferation of mesenchymal-like mesothelial cells, accumulation of AGE, de novo expression of αSMA and RAGE and gene expression of type I collagen, TGF-β1, Snail and MMP-2, whereas both MGO and RF alone had, at most, marginal effects on the changes in these biological parameters. CONCLUSIONS In the present study, the adverse effects of MGO on the peritoneum became more prominent under conditions of a uremic milieu. These findings imply that MGO and uremia act cooperatively to induce PF.
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Affiliation(s)
- Akira Onishi
- Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan
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41
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Rouberol F, Chiquet C. [Proliferative vitreoretinopathy: pathophysiology and clinical diagnosis]. J Fr Ophtalmol 2014; 37:557-65. [PMID: 24997864 DOI: 10.1016/j.jfo.2014.04.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Revised: 04/22/2014] [Accepted: 04/23/2014] [Indexed: 12/24/2022]
Abstract
Proliferative vitreoretinopathy (PVR) remains one of the most common causes of failed retinal detachment (RD) surgery. Many histological and clinical studies have highlighted the chain of events leading to PVR: cellular migration into the vitreous cavity, cellular differentiation, myofibroblast proliferation and activation, synthesis of extracellular matrix proteins, then contraction of preretinal tissues. The development of PVR can be explained schematically by cellular exposure to growth factors and cytokines (particularly retinal pigment epithelial cells and glial cells), in the context of break-down of the blood-retinal barrier (inflammation, choroidal detachment, iatrogenic effect of cryotherapy and surgery) and of cellular contact with the vitreous. Although the pathophysiology of PVR is now better understood, its severity remains an issue. A systematic search for preoperative PVR risk factors allows the most suitable therapeutic option to be chosen.
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Affiliation(s)
- F Rouberol
- Centre d'ophtalmologie Kléber, 50, cours Franklin-Roosevelt, 69006 Lyon, France
| | - C Chiquet
- Clinique universitaire d'ophtalmologie, université J.-Fourier, CHU de Grenoble, CS 2017, 38043 Grenoble cedex 09, France.
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42
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Nakamoto H, Hamada C, Shimaoka T, Sekiguchi Y, Io H, Kaneko K, Horikoshi S, Tomino Y. Accumulation of advanced glycation end products and beta 2-microglobulin in fibrotic thickening of the peritoneum in long-term peritoneal dialysis patients. J Artif Organs 2013; 17:60-8. [PMID: 24337623 DOI: 10.1007/s10047-013-0741-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2012] [Accepted: 10/27/2013] [Indexed: 12/18/2022]
Abstract
Characteristics of pathological alterations in long-term peritoneal dialysis (PD) are thickening of submesothelial compact (SMC) zone, small-vessel vasculopathy, and loss of mesothelial cells. Bioincompatible PD fluid plays crucial roles in peritoneal injury. Encapsulating peritoneal sclerosis (EPS), a rare and serious complication, occurred in patients on long-term PD or frequent peritonitis episodes, and ~50 % of EPS developed after PD cessation. We hypothesized that PD-related peritoneal injury factors induced by bioincompatible PD fluid accumulated in the peritoneum and might induce EPS. We therefore examined the accumulation of advanced glycation end products (AGE) and beta 2-microglobulin (β2M) in peritoneum and evaluated the relationship between their accumulation, clinical parameters, and outcome after PD cessation. Forty-five parietal peritoneal specimens were obtained from 28 PD patients, 14 uremic patients, and three patients with normal kidney function. The peritoneal equilibration test was used for peritoneal function. AGE- and β2M-expressing areas were found in vascular walls, perivascular areas, and the deep layer of the SMC in short-term PD patients and extended over the entire SMC in long-term patients. Peritonitis and prolonged PD treatment aggravated peritoneal thickening and the proportion of AGE-expressing areas. The proportion of β2M-expressing areas was increased in long-term PD patients. Thickening of the SMC and the proportions of AGE- and β2M-expressing areas were not related to ascites or EPS after PD withdrawal. It appears that the increased proportion of AGE and β2M deposition induced by long-term exposure of PD fluid may be a marker of peritoneal injury.
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Affiliation(s)
- Hirotaka Nakamoto
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
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Kinashi H, Ito Y, Mizuno M, Suzuki Y, Terabayashi T, Nagura F, Hattori R, Matsukawa Y, Mizuno T, Noda Y, Nishimura H, Nishio R, Maruyama S, Imai E, Matsuo S, Takei Y. TGF-β1 promotes lymphangiogenesis during peritoneal fibrosis. J Am Soc Nephrol 2013; 24:1627-42. [PMID: 23990681 PMCID: PMC3785267 DOI: 10.1681/asn.2012030226] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2012] [Accepted: 05/01/2013] [Indexed: 12/12/2022] Open
Abstract
Peritoneal fibrosis (PF) causes ultrafiltration failure (UFF) and is a complicating factor in long-term peritoneal dialysis. Lymphatic reabsorption also may contribute to UFF, but little is known about lymphangiogenesis in patients with UFF and peritonitis. We studied the role of the lymphangiogenesis mediator vascular endothelial growth factor-C (VEGF-C) in human dialysate effluents, peritoneal tissues, and peritoneal mesothelial cells (HPMCs). Dialysate VEGF-C concentration correlated positively with the dialysate-to-plasma ratio of creatinine (D/P Cr) and the dialysate TGF-β1 concentration. Peritoneal tissue from patients with UFF expressed higher levels of VEGF-C, lymphatic endothelial hyaluronan receptor-1 (LYVE-1), and podoplanin mRNA and contained more lymphatic vessels than tissue from patients without UFF. Furthermore, mesothelial cell and macrophage expression of VEGF-C increased in the peritoneal membranes of patients with UFF and peritonitis. In cultured mesothelial cells, TGF-β1 upregulated the expression of VEGF-C mRNA and protein, and this upregulation was suppressed by a TGF-β type I receptor (TGFβR-I) inhibitor. TGF-β1-induced upregulation of VEGF-C mRNA expression in cultured HPMCs correlated with the D/P Cr of the patient from whom the HPMCs were derived (P<0.001). Moreover, treatment with a TGFβR-I inhibitor suppressed the enhanced lymphangiogenesis and VEGF-C expression associated with fibrosis in a rat model of PF. These results suggest that lymphangiogenesis associates with fibrosis through the TGF-β-VEGF-C pathway.
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Affiliation(s)
| | - Yasuhiko Ito
- Departments of Nephrology and Renal Replacement Therapy
| | | | | | | | - Fumiko Nagura
- Departments of Nephrology and Renal Replacement Therapy
| | | | | | - Tomohiro Mizuno
- Division of Clinical Sciences and Neuropsychopharmacology, Meijyo University Graduate School of Medicine, Nagoya, Japan
| | - Yukihiro Noda
- Division of Clinical Sciences and Neuropsychopharmacology, Meijyo University Graduate School of Medicine, Nagoya, Japan
| | - Hayato Nishimura
- Department of Nephrology, Toyota Kosei Hospital, Toyota, Japan; and
| | - Ryosuke Nishio
- Department of Emergency Medicine, Kyoto University Hospital, Kyoto, Japan
| | | | - Enyu Imai
- Departments of Nephrology and Renal Replacement Therapy
| | | | - Yoshifumi Takei
- Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan
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44
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Peritoneal fibrosis and the putative role of decorin. Int J Organ Transplant Med 2013. [DOI: 10.1016/j.hkjn.2013.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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45
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Inflammation, neoangiogenesis and fibrosis in peritoneal dialysis. Clin Chim Acta 2013; 421:46-50. [DOI: 10.1016/j.cca.2013.02.027] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2012] [Revised: 02/14/2013] [Accepted: 02/19/2013] [Indexed: 11/22/2022]
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Goodwin M, Herath C, Jia Z, Leung C, Coughlan MT, Forbes J, Angus P. Advanced glycation end products augment experimental hepatic fibrosis. J Gastroenterol Hepatol 2013; 28:369-76. [PMID: 23173780 DOI: 10.1111/jgh.12042] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/02/2012] [Indexed: 01/03/2023]
Abstract
BACKGROUND AND AIMS Advanced glycation end products (AGEs) are nonenzymatic modifications of proteins by reducing sugars. These compounds accumulate in a number of chronic disease states, contributing to tissue injury via several mechanisms, including activation of the receptor for advanced glycation end products (RAGE). We aimed to investigate whether AGEs can exacerbate chronic liver injury and contribute to hepatic fibrosis. METHODS We initially studied the effects of chronic hepatic exposure to high levels of AGEs given intraperitoneally as AGE-rat serum albumin. In a separate experiment, we examined the impact of high AGE exposure in rats following bile duct ligation (BDL). RESULTS In normal rats, chronic AGE-rat serum albumin administration induced significant increases in α-smooth muscle actin gene and protein expression but did not induce fibrosis or biochemical evidence of liver injury. However, in BDL animals, AGE-bovine serum albumin administration significantly increased hepatic fibrosis as evidenced by increased collagen content and α-smooth muscle actin expression, compared with BDL alone. Furthermore, AGEs increased hepatic oxidative stress and receptor for advanced glycation end products gene expression. CONCLUSIONS These findings suggest that AGEs may contribute to the pathogenesis of chronic liver injury and fibrosis.
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Affiliation(s)
- Michelle Goodwin
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia.
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Yang CY, Chau YP, Lee HT, Kuo HY, Lee OK, Yang AH. Cannabinoid receptors as therapeutic targets for dialysis-induced peritoneal fibrosis. Am J Nephrol 2013; 37:50-8. [PMID: 23296044 DOI: 10.1159/000345726] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2012] [Accepted: 11/07/2012] [Indexed: 12/21/2022]
Abstract
BACKGROUND Long-term exposure to bioincompatible peritoneal dialysis solutions is frequently complicated with peritoneal fibrosis and ultrafiltration failure. As cannabinoid receptor (CBR) ligands have been reported to be beneficial to ameliorate the process of liver fibrosis, we strove to investigate their therapeutic potential to prevent peritoneal fibrosis. METHODS We used the rat model of peritoneal fibrosis induced by intraperitoneal injection of methylglyoxal and in vitro mesothelial cell culture to test the effects of CBR ligands, including the type 1 CBR (CB(1)R) antagonist and the type 2 CBR (CB(2)R) agonist. RESULTS In the methylglyoxal model, both intraperitoneal CB(1)R antagonist (AM281) and CB(2)R agonist (AM1241) treatment significantly ameliorated peritoneal fibrosis. In addition, CB(1)R antagonist was able to alleviate TGF-β(1)-induced dedifferentiation of mesothelial cells and to maintain epithelial integrity in vitro. CONCLUSIONS Intraperitoneal administration of CBR ligands (CB(1)R antagonist and CB(2)R agonist) offers a potential therapeutic strategy to reduce dialysis-induced peritoneal fibrosis and to prolong the peritoneal survival in peritoneal dialysis patients.
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Affiliation(s)
- Chih-Yu Yang
- Division of Nephrology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
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48
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Boudouris G, Verginadis II, Simos YV, Zouridakis A, Ragos V, Karkabounas SC, Evangelou AM. Oxidative stress in patients treated with continuous ambulatory peritoneal dialysis (CAPD) and the significant role of vitamin C and E supplementation. Int Urol Nephrol 2012; 45:1137-44. [DOI: 10.1007/s11255-012-0334-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2012] [Accepted: 11/09/2012] [Indexed: 11/29/2022]
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49
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Mácsai E. Skin autofluorescence measurement in diabetological and nephrological clinical practice. Orv Hetil 2012; 153:1651-7. [DOI: 10.1556/oh.2012.29453] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Formation of advanced glycation end-products plays role in the pathogenesis of diabetic complications and related ongoing connective tissue degeneration as part of atherosclerosis and chronic kidney disease. The cumulative metabolic burden of patients can be measured in few minutes using a recently developed non-invasive mobile device, which has been developed for the evaluation of fluorescent advanced glycation end-product molecules in skin. The variation of skin autofluorescence measurement is about 10%, and its predictive value in cardiovascular events overcomes conventional glycemic markers even in chronic kidney disease population. In the early stages of diabetes it seems to be an effective screening tool, and in overt diabetes signifies micro- and macrovascular complications. This method is unadaptable in systemic autoimmune diseases, generalised dermatological illnesses and hepatobiliary pathological conditions leading to icterus. Significant correlation has been found between skin autofluorescence and pulse wave velocity due to glycation of vascular wall structure proteins and consequent arterial matrix rigidity. Orv. Hetil., 2012, 153, 1651–1657.
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Affiliation(s)
- Emília Mácsai
- Csolnoky Ferenc Oktatókórház Belgyógyászati Centrum Veszprém Kórház u. 1. 8200
- BBRAUN 3. Számú Dialízisközpont Veszprém
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Robinson AB, Stogsdill JA, Lewis JB, Wood TT, Reynolds PR. RAGE and tobacco smoke: insights into modeling chronic obstructive pulmonary disease. Front Physiol 2012; 3:301. [PMID: 22934052 PMCID: PMC3429072 DOI: 10.3389/fphys.2012.00301] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2012] [Accepted: 07/10/2012] [Indexed: 12/31/2022] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a progressive condition characterized by chronic airway inflammation and airspace remodeling, leading to airflow limitation that is not completely reversible. Smoking is the leading risk factor for compromised lung function stemming from COPD pathogenesis. First- and second-hand cigarette smoke contain thousands of constituents, including several carcinogens and cytotoxic chemicals that orchestrate chronic lung inflammation and destructive alveolar remodeling. Receptors for advanced glycation end-products (RAGE) are multi-ligand cell surface receptors primarily expressed by diverse lung cells. RAGE expression increases following cigarette smoke exposure and expression is elevated in the lungs of patients with COPD. RAGE is responsible in part for inducing pro-inflammatory signaling pathways that culminate in expression and secretion of several cytokines, chemokines, enzymes, and other mediators. In the current review, new transgenic mouse models that conditionally over-express RAGE in pulmonary epithelium are discussed. When RAGE is over-expressed throughout embryogenesis, apoptosis in the peripheral lung causes severe lung hypoplasia. Interestingly, apoptosis in RAGE transgenic mice occurs via conserved apoptotic pathways also known to function in advanced stages of COPD. RAGE over-expression in the adult lung models features of COPD including pronounced inflammation and loss of parenchymal tissue. Understanding the biological contributions of RAGE during cigarette smoke-induced inflammation may provide critically important insight into the pathology of COPD.
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Affiliation(s)
| | | | | | | | - Paul R. Reynolds
- Department of Physiology and Developmental Biology, Brigham Young UniversityProvo, UT, USA
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