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Molecular and Pathophysiological Mechanisms of Peritoneal Fibrosis in Peritoneal Dialysis

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 March 2025 | Viewed by 7680

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Dr. Kimio Watanabe

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University Hospital Blood Purification, Tohoku University, Sendai 980-8577, Japan
Interests: nephrology

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Dear Colleagues,

Peritoneal dialysis (PD) is an efficient renal replacement therapy for patients with end-stage kidney disease. However, long-term PD causes peritoneal fibrosis accompanying morphologic and functional changes in the peritoneal membrane. Peritoneal fibrosis is one of the important causes of PD technique failure, but its molecular and pathophysiological mechanisms remain largely unclear. A number of studies demonstrated that TGF-β/Smad signaling is the key mediator associated with progressive peritoneal fibrosis. The high activation of this pathway increases the collagen deposition and thickening of the peritoneal membrane. The most well-known Smad-independent pathways include protein kinase C (PKC), the extracellular signal-regulated kinase (ERK), the c-Jun N-terminal kinase (JNK), and the phosphatidylinositol-3-kinase (PI3K). Accumulating evidence shows that TGF-β/Smad-dependent or -independent micro-RNAs can also regulate peritoneal fibrosis. Bioincompatible dialysis solution, which induces chronic peritoneal inflammation, is considered the main factor for peritoneal fibrosis. Continuous exposure to bioincompatible dialysis solution induces the mesothelial-to-mesenchymal transition (MMT) along with inflammation and angiogenesis. We take particular interest in original papers and reviews that report on the relevance of molecular and pathophysiological mechanisms involved in the pathogenesis of peritoneal fibrosis in PD.

Dr. Kimio Watanabe
Guest Editor

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Keywords

peritoneal fibrosis
peritoneal dialysis
TGF-β/smad signaling
bioincompatible dialysis solution
peritoneal inflammation
mesothelial-to-mesenchymal transition

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Published Papers (4 papers)

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Research

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19 pages, 4005 KiB

Open AccessArticle

High Salt Promotes Inflammatory and Fibrotic Response in Peritoneal Cells

by Domonkos Pap, Csenge Pajtók, Apor Veres-Székely, Beáta Szebeni, Csenge Szász, Péter Bokrossy, Réka Zrufkó, Ádám Vannay, Tivadar Tulassay and Attila J. Szabó

Int. J. Mol. Sci. 2023, 24(18), 13765; https://doi.org/10.3390/ijms241813765 - 6 Sep 2023

Cited by 1 | Viewed by 1930

Abstract

Recent studies draw attention to how excessive salt (NaCl) intake induces fibrotic alterations in the peritoneum through sodium accumulation and osmotic events. The aim of our study was to better understand the underlying mechanisms. The effects of additional NaCl were investigated on human primary mesothelial cells (HPMC), human primary peritoneal fibroblasts (HPF), endothelial cells (HUVEC), immune cells (PBMC), as well as ex vivo on peritoneal tissue samples. Our results showed that a high-salt environment and the consequently increased osmolarity increase the production of inflammatory cytokines, profibrotic growth factors, and components of the renin–angiotensin–aldosterone system, including IL1B, IL6, MCP1, TGFB1, PDGFB, CTGF, Renin and Ace both in vitro and ex vivo. We also demonstrated that high salt induces mesenchymal transition by decreasing the expression of epithelial marker CDH1 and increasing the expression of mesenchymal marker ACTA2 and SNAIL1 in HPMCs, HUVECs and peritoneal samples. Furthermore, high salt increased extracellular matrix production in HPFs. We demonstrated that excess Na⁺ and the consequently increased osmolarity induce a comprehensive profibrotic response in the peritoneal cells, thereby facilitating the development of peritoneal fibrosis. Full article

(This article belongs to the Special Issue Molecular and Pathophysiological Mechanisms of Peritoneal Fibrosis in Peritoneal Dialysis)

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16 pages, 4678 KiB

Open AccessArticle

Peritoneal Expression of Membrane Complement Regulators Is Decreased in Peritoneal Dialysis Patients with Infected Peritonitis

by Sosuke Fukui, Masashi Mizuno, Mitsuhiro Tawada, Yasuhiro Suzuki, Hiroshi Kojima, Yoshihisa Matsukawa, Masaki Imai, Hangsoo Kim, Hiroshi Kinashi, Makoto Mizutani, Kenichi Minoshima, Shoichi Maruyama and Yasuhiko Ito

Int. J. Mol. Sci. 2023, 24(11), 9146; https://doi.org/10.3390/ijms24119146 - 23 May 2023

Cited by 1 | Viewed by 1615

Abstract

In peritoneal dialysis (PD) patients, fungi and Pseudomonas aeruginosa are considered important causative microorganisms for peritonitis with poor prognosis. Our objective was to explore expressions of membrane complement (C) regulators (CRegs) and tissue injuries in the peritoneum of patients with PD-related peritonitis, including fungal and Pseudomonas aeruginosa peritonitis. In peritoneal biopsy tissues obtained at PD catheter removal, we investigated the severity of peritonitis-associated peritoneal injuries and the expression of CRegs, CD46, CD55, and CD59 against peritoneal tissues without any episode of peritonitis. In addition, we evaluated peritoneal injuries among fungal and Pseudomonas aeruginosa-peritonitis (P1) and Gram-positive bacterial peritonitis (P2). We also observed deposition of C activation products such as activated C and C5b-9 and measured sC5b-9 in the PD fluid of patients. As a result, the severity of peritoneal injuries correlated inversely with the expression of peritoneal CRegs. Peritoneal CReg expression in peritonitis was significantly reduced compared to no peritonitis. Peritoneal injuries were more severe in P1 than in P2. CReg expression was further decreased and C5b-9 further increased in P1 than in P2. In conclusion, severe peritoneal injuries due to fungal and Pseudomonas aeruginosa-peritonitis decreased CReg expression and increased deposition of activated C3 and C5b-9 in the peritoneum, suggesting that peritonitis, particularly fungal and Pseudomonas aeruginosa-peritonitis, might induce susceptibility to further peritoneal injuries due to excessive C activation. Full article

(This article belongs to the Special Issue Molecular and Pathophysiological Mechanisms of Peritoneal Fibrosis in Peritoneal Dialysis)

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13 pages, 2420 KiB

Open AccessArticle

The Transfer of the Hepatocyte Growth Factor Gene by Macrophages Ameliorates the Progression of Peritoneal Fibrosis in Mice

by Yoko Obata, Katsushige Abe, Masanobu Miyazaki, Takehiko Koji, Yasuhiko Tabata and Tomoya Nishino

Int. J. Mol. Sci. 2023, 24(8), 6951; https://doi.org/10.3390/ijms24086951 - 9 Apr 2023

Cited by 3 | Viewed by 1943

Abstract

Growing evidence indicates that hepatocyte growth factor (HGF) possesses potent antifibrotic activity. Furthermore, macrophages migrate to inflamed sites and have been linked to the progression of fibrosis. In this study, we utilized macrophages as vehicles to express and deliver the HGF gene and investigated whether macrophages carrying the HGF expression vector (HGF-M) could suppress peritoneal fibrosis development in mice. We obtained macrophages from the peritoneal cavity of mice stimulated with 3% thioglycollate and used cationized gelatin microspheres (CGMs) to produce HGF expression vector-gelatin complexes. Macrophages phagocytosed these CGMs, and gene transfer into macrophages was confirmed in vitro. Peritoneal fibrosis was induced by intraperitoneal injection of chlorhexidine gluconate (CG) for three weeks; seven days after the first CG injection, HGF-M was administered intravenously. Transplantation of HGF-M significantly suppressed submesothelial thickening and reduced type III collagen expression. Moreover, in the HGF-M-treated group, the number of α-smooth muscle actin- and TGF-β-positive cells were significantly lower in the peritoneum, and ultrafiltration was preserved. Our results indicated that the transplantation of HGF-M prevented the progression of peritoneal fibrosis and indicated that this novel gene therapy using macrophages may have potential for treating peritoneal fibrosis. Full article

(This article belongs to the Special Issue Molecular and Pathophysiological Mechanisms of Peritoneal Fibrosis in Peritoneal Dialysis)

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Review

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27 pages, 804 KiB

Open AccessReview

Pathophysiological Mechanisms of Peritoneal Fibrosis and Peritoneal Membrane Dysfunction in Peritoneal Dialysis

by Yasuhiko Ito, Ting Sun, Mitsuhiro Tawada, Hiroshi Kinashi, Makoto Yamaguchi, Takayuki Katsuno, Hangsoo Kim, Masashi Mizuno and Takuji Ishimoto

Int. J. Mol. Sci. 2024, 25(16), 8607; https://doi.org/10.3390/ijms25168607 - 7 Aug 2024

Cited by 1 | Viewed by 1185

Abstract

The characteristic feature of chronic peritoneal damage in peritoneal dialysis (PD) is a decline in ultrafiltration capacity associated with pathological fibrosis and angiogenesis. The pathogenesis of peritoneal fibrosis is attributed to bioincompatible factors of PD fluid and peritonitis. Uremia is associated with peritoneal membrane inflammation that affects fibrosis, neoangiogenesis, and baseline peritoneal membrane function. Net ultrafiltration volume is affected by capillary surface area, vasculopathy, peritoneal fibrosis, and lymphangiogenesis. Many inflammatory cytokines induce fibrogenic growth factors, with crosstalk between macrophages and fibroblasts. Transforming growth factor (TGF)-β and vascular endothelial growth factor (VEGF)-A are the key mediators of fibrosis and angiogenesis, respectively. Bioincompatible factors of PD fluid upregulate TGF-β expression by mesothelial cells that contributes to the development of fibrosis. Angiogenesis and lymphangiogenesis can progress during fibrosis via TGF-β–VEGF-A/C pathways. Complement activation occurs in fungal peritonitis and progresses insidiously during PD. Analyses of the human peritoneal membrane have clarified the mechanisms by which encapsulating peritoneal sclerosis develops. Different effects of dialysates on the peritoneal membrane were also recognized, particularly in terms of vascular damage. Understanding the pathophysiologies of the peritoneal membrane will lead to preservation of peritoneal membrane function and improvements in technical survival, mortality, and quality of life for PD patients. Full article

(This article belongs to the Special Issue Molecular and Pathophysiological Mechanisms of Peritoneal Fibrosis in Peritoneal Dialysis)

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