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Long-term exposure of the peritoneum to peritoneal dialysate results in pathophysiological changes in the anatomical organization of the peritoneum and progressive development of peritoneal fibrosis. This leads to a decline in peritoneal function and ultrafiltration failure, ultimately necessitating the discontinuation of peritoneal dialysis, severely limiting the potential for long-term maintenance. Additionally, encapsulating peritoneal sclerosis, a serious consequence of peritoneal fibrosis, resulting in patients discontinuing PD and significant mortality. The causes and mechanisms underlying peritoneal fibrosis in patients undergoing peritoneal dialysis remain unknown, with no definitive treatment available. However, abnormal activation of the immune system appears to be involved in altering the structure of the peritoneum and promoting fibrotic changes. Macrophage infiltration and polarization are key contributors to pathological injury within the peritoneum, showing a strong correlation with the epithelial-to-mesenchymal transition of mesothelial cells and driving the process of fibrosis. This article discusses the role and mechanisms underlying macrophage activation-induced peritoneal fibrosis resulting from PD by analyzing relevant literature from the past decade and provides an overview of recent therapeutic approaches targeting macrophages to treat this condition.

Peritoneal dialysis (PD) is a successful renal replacement therapy for end-stage renal disease. Continuous infiltration of bioincompatible PD fluid causes mesothelial-mesenchymal transition (MMT) of peritoneal mesothelial cells (PMCs), leading to peritoneal fibrosis (PF). DNA methylation has been characterized as an important regulatory mechanism on multiple fibrosis. However, the mechanisms by which DNA methylation regulates PF are not fully understood resulting in a lack of disease-modifying drugs. Astragalus membranaceus (Astragalus) is naturally phytomedicine that has immunoregulation properties. The study aimed to elucidate the underlying mechanisms of Astragalus in regulating DNA methylation and anti-PF capabilities. In vivo PD rat models were established by inducing with high-glucose PD fluid and Astragalus was intraperitoneal injection. Global DNA methylation sequencing was used to compare the DNA methylation status between control and PF rat models. Methylation profiles and KEGG analysis were identified a possible methylated target gene and its correlation pathway. Through real-time PCR and western blotting, candidate markers and pathways were validated in vivo and in vitro. Chromatin immunoprecipitation and luciferase assays were used to identify the prediction of DNA methyltransferase (Dnmts) binding with methylated target gene. The functions of the validated pathways were further investigated using the knockdown or overexpression strategy. In vivo and in vitro, Astragalus treatment showed a protective effect against PF and Dnmts, characterized by improving pathological manifestation, ameliorating MMT markers, and reducing Dnmt1/3a proteins. Inhibitor of DNA-binding 2 (ID2) was investigated in target gene by integrating the mRNA and methylation profiles involved in PF and Astragalus treatment. PF induced the methylation of ID2 that resulted in recruitment of the Dnmt3a and decreased ID2 expression. The increased ID2 expression in response to Astragalus is a consequence of demethylation in promoter. In addition, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway correlated with PF, knockdown or overexpression of ID2 regulated this pathway and MMT of PMCs. Astragalus ameliorated PF by targeting Dnmt3a mediated ID2 promoter via PI3K/Akt signaling pathway. The epigenetic regulation of DNA methylation existed the critical role in attenuating PF.

When chronic kidney disease (CKD) progresses to end-stage renal disease (ESRD), peritoneal dialysis (PD) can serve as an effective alternative therapy, but it also has its limitations. Peritoneal fibrosis (PF), a PD-related complication, is one of the major and serious complications of long-term PD that can lead to ultrafiltration failure, severely impacting the efficacy of PD treatment. At present, most of the research on the molecular mechanisms of fibrosis focuses on the liver and kidney, but there is relatively little research on PF for identifying anti-fibrotic targets. Histone deacetylase (HDAC), as an enzyme that exerts transcriptional regulation through deacetylation, when activated can lead to the occurrence and development of inflammation and fibrosis. This review aims to assess the effects of HDAC and HDAC inhibitors on peritoneal inflammation and fibrosis in PF. Therefore, we reviewed the recent progress in PF treatment, focusing on understanding the characteristics and functions of HDAC and their interactions with the extracellular matrix in PF progression, and explored the crucial role of HDAC in regulating fibrosis regression. Additionally, we explored future research directions to identify potential methods for treating PF.

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.

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.

Dapagliflozin (DAPA), an SGLT-2 inhibitor, shows peritoneal protection and can alleviate high glucose-induced peritoneal fibrosis. Yet, its precise molecular mechanism is unknown. This study aims to explore DAPA’s protective effect on the peritoneum and its underlying mechanism. In vitro, human peritoneal mesothelial cells (HPMCs) were isolated from peritoneal dialysate and cultured. HMrSV5 cells were stimulated with 2.5% D-Glucose (high glucose, HG) for 48 h, then cultured in D-glucose DMEM medium with or without DAPA. To assess SGLT2i-induced ENKUR down-regulation, HMrSV5 cells were treated with DAPA for 24 h while overexpressing ENKUR. In vivo, six-week-old male Sprague-Dawley rats were treated with high-glucose dialysate via an intraperitoneal catheter, with or without addition of DAPA. Changes in SGLT2, ENKUR, PI3K/AKT pathways, and EMT markers were evaluated in HPMCs and the rat model. As dialysis duration increases the morphology of the cells transitioned from a cobblestone appearance to a spindle shape. Immunofluorescence analysis confirmed the mesothelial cell origin and revealed an upregulation of ENKUR and the PI3K/AKT signaling pathway, which are associated with the occurrence of EMT. DAPA was found to decrease the expression of ENKUR and inhibit the activation of the PI3K/AKT pathway induced by high glucose in HMrSV5 cells. In rats subjected to PD, we observed a reduction in ultrafiltration capacity, an increase in peritoneal thickness, and elevated levels of SGLT2, ENKUR, PI3K/AKT and EMT markers. Notably, these alterations were mitigated by intragastric administration of DAPA. DAPA effectively ameliorates high glucose-induced peritoneal fibrosis through downregulation of ENKUR/PI3K/AKT signaling pathway.

Long‐term peritoneal dialysis (PD) leads to peritoneal damage and chronic inflammation, resulting in peritoneal fibrosis (PF). Emerging evidence suggests that yes‐associated protein (YAP) is a key player in fibrogenesis across various organs. However, its role in PD‐induced PF remains unclear. We used NIH/3T3 cells, primary mouse fibroblasts, and conditional YAP knockout (CKO) mice with glioma‐associated oncogene 1 (Gli1)‐specific YAP deletion. The effects of YAP knockdown and verteporfin, a YAP inhibitor, on fibroblast‐to‐mesenchymal transition (FMT) and angiogenesis were evaluated. Transforming growth factor‐beta (TGF‐β) induced YAP expression and promoted fibroblast‐to‐myofibroblast transition (FMT) in 3T3 fibroblasts, upregulating collagen 1A1, α‐smooth muscle actin (α‐SMA), and connective tissue growth factor (CTGF). YAP knockdown and verteporfin treatment reduced these FMT markers and inhibited smad2/3 phosphorylation. In vivo, YAP and Gli1‐expressing cells were upregulated in PD‐induced PF. Conditional YAP knockout in Gli1+ cells and verteporfin treatment significantly reduced fibrosis and α‐SMA, collagen 1, TGF‐β, CTGF, and phosphorylated smad2/3 expression in the peritoneum and peritoneal angiogenesis. YAP plays a pivotal role in FMT during PD‐induced PF. Conditional YAP deletion in Gli1‐expressing cells and verteporfin treatment represent promising antifibrotic strategies for long‐term PD patients.

Peritoneal fibrosis (PF) is a major complication of long-term peritoneal dialysis, leading to ultrafiltration failure and technique dropout, highlighting the urgent need for therapies that can preserve peritoneal membrane function and longevity. The present study evaluated the effectiveness of dulaglutide in preserving the functional integrity and durability of the peritoneum while inhibiting PF. In vitro Met-5A cells showed significant upregulation of inflammatory, oxidative stress, intracellular and mitochondrial reactive oxygen species (ROS), fibrotic, intracellular cytoskeletal, apoptotic and epithelial-mesenchymal transition (EMT) biomarkers, and dipeptidyl peptidase 4 (DPP4), following stimulation with a uremic toxin (p-Cresol), PF inducer [chlorhexidine gluconate (CG)] or endotoxin [lipopolysaccharide (LPS)]. Notably, these effects were significantly suppressed by dulaglutide or TGF-β/DPP4 double silencing. Furthermore, cell viability and glucagon-like peptide 1 (GLP-1) expression displayed an opposite pattern to ROS among the groups. Sprague-Dawley rats were divided into the following groups: i) Sham control (SC); ii) chronic kidney disease (CKD); iii) CKD + CG (mimicking renal failure and PF); and iv) CKD + CG + dulaglutide, and were euthanized by day 42. At this time point, the highest levels of peritoneal protein expression levels of oxidative stress (NOX-1, NOX-2 and DPP4), inflammation (NF-κB and TNF-α), angiogenesis (CD31 and von Willebrand factor) and EMT (TGF-β, Snail, β-catenin, vimentin, phosphorylated-Smad3, α-smooth muscle actin, collagen I, N-cadherin and fibronectin) factors; and cellular expression levels of fibrosis and inflammation markers, were observed in the CKD + CG group, the lowest were detected in the SC group, and the levels were significantly reduced in the CKD + CG + dulaglutide group compared with those in the CKD group. Furthermore, the expression levels of antioxidant proteins (nuclear factor erythroid 2-related factor 2, NAD(P)H quinone oxidoreductase 1 and GLP-1 receptor) exhibited an opposite trend to ROS-associated proteins among the groups. Additional Sprague-Dawley rats were categorized into the following groups: i) SC; ii) LPS-induced peritonitis; iii) LPS-induced peritonitis + dulaglutide, and were euthanized by day 5 after peritonitis induction. At this time point, flow cytometry revealed significantly increased levels of inflammatory cells (CD11b/c+, myeloperoxidase+ and Ly6G+ cells) in the circulation and abdominal fluid, and increased peritoneal permeability in the LPS-induced peritonitis group compared with those in the SC group; these levels were significantly reversed in the LPS-induced peritonitis + dulaglutide group. In conclusion, dulaglutide may effectively maintain peritoneal integrity primarily by suppressing inflammation, oxidative stress, EMT and fibrosis.

Encapsulating peritoneal sclerosis (EPS) is a life-threatening complication of long-term peritoneal dialysis (PD), which may even occur after patients have switched to hemodialysis (HD) or undergone kidney transplantation. The incidence of EPS varies across the globe and increases with PD vintage. Causative factors are the chronic exposure to bioincompatible PD solutions, which cause long-term modifications of the peritoneum, a high peritoneal transporter status involving high glucose concentrations, peritonitis episodes, and smoldering peritoneal inflammation. Additional potential causes are predisposing genetic factors and some medications. Clinical symptoms comprise signs of intestinal obstruction and a high peritoneal transporter status with incipient ultrafiltration failure. In radiological, macro-, and microscopic studies, a massively fibrotic and calcified peritoneum enclosed the intestine and parietal wall in such cases. Empirical treatments commonly used are corticosteroids and tamoxifen, which has fibrinolytic properties. Immunosuppressants like azathioprine, mycophenolate mofetil, or mTOR inhibitors may also help with reducing inflammation, fibrin deposition, and collagen synthesis and maturation. In animal studies, N-acetylcysteine, colchicine, rosiglitazone, thalidomide, and renin-angiotensin system (RAS) inhibitors yielded promising results. Surgical treatment has mainly been performed in severe cases of intestinal obstruction, with varying results. Mortality rates are still 25–55% in adults and about 14% in children. To reduce the incidence of EPS and improve the outcome of this devastating complication of chronic PD, vigorous consideration of the risk factors, early diagnosis, and timely discontinuation of PD and therapeutic interventions are mandatory, even though these are merely based on empirical evidence.

Mesenchymal stem cells (MSCs) are multipotent adult stem cells that have regenerative capability and exert paracrine actions on damaged tissues. Since peritoneal fibrosis is a serious complication of peritoneal dialysis, we tested whether MSCs suppress this using a chlorhexidine gluconate model in rats. Although MSCs isolated from green fluorescent protein–positive rats were detected for only 3 days following their injection, immunohistochemical staining showed that MSCs suppressed the expression of mesenchymal cells, their effects on the deposition of extracellular matrix proteins, and the infiltration of macrophages for 14 days. Moreover, MSCs reduced the functional impairment of the peritoneal membrane. Cocultures of MSCs and human peritoneal mesothelial cells using a Transwell system indicated that the beneficial effects of MSCs on the glucose-induced upregulation of transforming growth factor-β1(TGF-β1) and fibronectin mRNA expression in the human cells were likely due to paracrine actions. Preincubation in MSC-conditioned medium suppressed TGF-β1-induced epithelial-to-mesenchymal transition, α-smooth muscle actin, and the decrease in zonula occludens-1 in cultured human peritoneal mesothelial cells. Although bone morphogenic protein 7 was not detected, MSCs secreted hepatocyte growth factor and a neutralizing antibody to this inhibited TGF-β1 signaling. Thus, our findings imply that MSCs ameliorate experimental peritoneal fibrosis by suppressing inflammation and TGF-β1 signaling in a paracrine manner.