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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.

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) can be used as renal replacement therapy when chronic kidney disease (CKD) progresses to end-stage renal disease. However, peritoneal fibrosis (PF) is a major cause of PD failure. Studies have demonstrated that PD fluid contains a significantly larger numbers of macrophages compared with the healthy individuals. During PD, macrophages can secrete cytokines to keep peritoneal tissue in sustained low-grade inflammation, and participate in the regulation of fibrosis-related signaling pathways, such as NF-κB, TGF-β/Smad, IL4/STAT6, and PI3K/AKT. A series of basic pathological changes occurs in peritoneal tissues, including epithelial mesenchymal transformation, overgeneration of neovasculature, and abnormal deposition of extracellular matrix. This review focuses on the role of macrophages in promoting PF during PD, summarizes the targets of macrophage-related inhibition of fibrosis, and provides new ideas for clinical research on delaying PF, maintaining the function and integrity of peritoneum, prolonging duration of PD as a renal replacement modality, and achieving longer survival in CKD patients.

Lymphatic vessels drain excess tissue fluids to maintain the interstitial environment. Lymphatic capillaries develop during the progression of tissue fibrosis in various clinical and pathological situations, such as chronic kidney disease, peritoneal injury during peritoneal dialysis, tissue inflammation, and tumor progression. The role of fibrosis-related lymphangiogenesis appears to vary based on organ specificity and etiology. Signaling via vascular endothelial growth factor (VEGF)-C, VEGF-D, and VEGF receptor (VEGFR)-3 is a central molecular mechanism for lymphangiogenesis. Transforming growth factor-β (TGF-β) is a key player in tissue fibrosis. TGF-β induces peritoneal fibrosis in association with peritoneal dialysis, and also induces peritoneal neoangiogenesis through interaction with VEGF-A. On the other hand, TGF-β has a direct inhibitory effect on lymphatic endothelial cell growth. We proposed a possible mechanism of the TGF-β–VEGF-C pathway in which TGF-β promotes VEGF-C production in tubular epithelial cells, macrophages, and mesothelial cells, leading to lymphangiogenesis in renal and peritoneal fibrosis. Connective tissue growth factor (CTGF) is also involved in fibrosis-associated renal lymphangiogenesis through interaction with VEGF-C, in part by mediating TGF-β signaling. Further clarification of the mechanism might lead to the development of new therapeutic strategies to treat fibrotic diseases.

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.

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.

One of the most common causes of peritoneal dialysis withdrawal is ultrafiltration failure which is characterized by peritoneal membrane thickening and fibrosis. Although previous studies have demonstrated the inhibitory effect of p38 MAPK inhibitors on peritoneal fibrosis in mice, it was unclear which specific cells contribute to peritoneal fibrosis. To investigate the role of p38 MAPK in peritoneal fibrosis more precisely, we examined the expression of p38 MAPK in human peritoneum and generated systemic inducible p38 MAPK knockout mice and macrophage-specific p38 MAPK knockout mice. Furthermore, the response to lipopolysaccharide (LPS) was assessed in p38 MAPK-knocked down RAW 264.7 cells to further explore the role of p38 MAPK in macrophages. We found that phosphorylated p38 MAPK levels were increased in the thickened peritoneum of both human and mice. Both chlorhexidine gluconate (CG)-treated systemic inducible and macrophage-specific p38 MAPK knockout mice ameliorated peritoneal thickening, mRNA expression related to inflammation and fibrosis, and the number of αSMA- and MAC-2-positive cells in the peritoneum compared to CG control mice. Reduction of p38 MAPK in RAW 264.7 cells suppressed inflammatory mRNA expression induced by LPS. These findings suggest that p38 MAPK in macrophages plays a critical role in peritoneal inflammation and thickening.

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.

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.

Peritoneal fibrosis has been linked to hypoxia-inducible factor 1-alpha (HIF-1α) as well as O-linked-N-acetylglucosaminylation (O-GlcNAcylation) in peritoneal dialysis (PD). Genistein, recognized for its HIF-1α inhibitory and antifibrotic effects, presents a potential intervention against peritoneal mesothelial-mesenchymal transition (MMT) as well as fibrosis in PD. This study employed human peritoneal mesothelial cells (HPMCs) together with adenine-induced chronic kidney disease (CKD) rats undergoing peritoneal dialysis to explore Genistein’s role in high glucose-induced peritoneal MMT and fibrosis. Our findings reveal that Genistein exerts anti-MMT and anti-fibrotic effects by inhibiting HIF-1α in HPMCs under high glucose conditions. Genistein inhibited O-GlcNAcylation status of HIF-1α through the mTOR/O-GlcNAc transferase (OGT) pathway, promoting its ubiquitination as well as the subsequent proteasomal degradation. In adenine-induced CKD rats undergoing peritoneal dialysis, Genistein suppressed the mTOR/OGT expression and reduced the abundance of O-GlcNAcylation along with HIF-1α in the peritoneum. Additionally, Genistein protected against increased peritoneal thickness, fibrosis, and angiogenesis, while improving peritoneal function. Based on our results, it could be inferred that Genistein might inhibit the abundance of HIF-1α via the mTOR/OGT pathway, thereby ameliorating MMT as well as fibrosis in PD.