Cell surface receptors, which are proteins embedded in cell membranes, are essential for regulating cellular responses to environmental cues and enabling signal transduction among cells. Cytokines or signaling proteins bind to their corresponding surface receptors, leading to downstream pathway alterations that regulate various processes, including cell proliferation, migration, phagocytosis, and cytokine production. Recent research has demonstrated the role of particular cell surface receptors in peritoneal fibrosis by modulating macrophage responses.

TLRs are a diverse family of receptors found on cell membranes or in cytoplasms of different immune cells, such as macrophages, natural killer cells, lymphocytes, endothelial and epithelial cells, and fibroblasts (71). TLR2 and TLR4 represent some of the initial immune responses employed by the host to combat infections, serving a crucial function in identifying pathogens. TLR4 is predominantly expressed on macrophages and serves as a critical inflammatory modulator. Studies have indicated that during PMC EMT, TLR4 signaling dependent on TRIF is triggered by the upregulation of transcription factors TRIF, IRF3, and IKK in M1 macrophages (64, 72). Activation of the TLR4 signaling pathway promotes synthesis of TGF-β and participates in post-inflammatory fibrosis formation (73, 74). In mice depleted of macrophages, peritoneal fibrosis was completely inhibited. However, after reperfusion with M1 macrophages, there was significant damage to peritoneal structure/function along with aggravated peritoneal fibrosis due to increased expression levels of TLR4 (17). Raby et al. (75) identified the expression of TLR2, TLR4, and C5aR in peritoneal macrophages and mesothelial cells, which are essential in facilitating pro-inflammatory and pro-fibrotic responses to bacterial infections. Additionally, the use of antibody blockade targeting TLR2, TLR4, or C5aR showed considerable inhibitory effects on the bacteria-induced release of pro-fibrotic and pro-inflammatory mediators by peritoneal leukocytes in cases of infection-related peritoneal fibrosis. To sum up, TLR2 and TLR4 have been identified as promising therapeutic targets for peritoneal fibrosis linked to PD, underscoring their importance in this area of research.

The tumor necrosis factor-like apoptosis weak inducers (TWEAK, TNFSF12), members of the structurally related cytokine TNF superfamily, have the ability to regulate apoptosis, inflammation, proliferation, and angiogenesis (76, 77). Fibroblast growth factor-induced 14 (Fn14) serves as a functional receptor for TWEAK, which is significantly upregulated and plays an essential role in tissue injury, repair, and remodeling processes (78). Sanz et al. (79) identified a rise in sTWEAK levels within the peritoneal effluents of patients experiencing PD peritonitis, which was associated with the count of peritoneal macrophages. Both mesothelial cells and macrophages express Fn14 receptors, making them potential targets for TWEAK. Peritoneal biopsy suggests that TWEAK/Fn14 may have detrimental effects on mesothelial injury, as well as peritoneal inflammation and fibrosis. Injection of TWEAK into the peritoneal cavity of mice induced an upregulation in MCP-1 expression, along with Fn14 and CCL21, in both peritoneal effluents and mesothelial cells, leading to increased recruitment of macrophages in subcutaneous tissue and resulting in peritoneal inflammation and fibrosis. Overall, these results indicate that the TWEAK/Fn14 pathway might play a role in inflammatory and fibrotic damage during peritonitis and PD by facilitating macrophage recruitment. The future necessitates further investigation into the modulation of peritoneal macrophages through inhibition of the TWEAK/Fn14 pathway, with the aim of enhancing peritoneal fibrosis management.

The fractalkine receptor CX3CR1, a surface protein found on leukocytes, is highly expressed in monocytes and macrophages (80). Besides its function in monocyte adhesion and recruitment, CX3CR1 also serves as a marker for TGF-β, a pro-fibrotic cytokine (81). Studies conducted in other organs and tissues have confirmed that interactions between CX3CR1 and CX3CL1 can promote fibrosis, whereas blocking CX3CR1 with medications can lower TGF-β expression in the kidney (81–83). However, CX3CR1 has also been reported to exhibit anti-fibrotic effects (84, 85). These different outcomes may be attributed to variations in local tissue expression levels of CX3CL1 and sex differences in receptor regulation (86). Interestingly, a recent study utilized flow cytometry and global transcriptome techniques to identify high levels of CX3CR1 expression in PD effluent (55). In both patients with PD and mouse models of PD, mesothelial cells were found to express CX3CL1, while peritoneal wall macrophages predominantly expressed CX3CR1. Interactions between macrophages and mesothelial cells lead to increased expression of CX3CL1 by mesothelial cells through the action of macrophage-expressed IL-1b and enhanced TGF-β production by mesothelial cells. This promotes dialysate-induced peritoneal fibrosis. Conversely, TGF-β promotes the expression of CX3CR1 on macrophages, thereby forming a pro-fibrotic feedback loop (87). Focusing on the interactions between CXCR and CXCL is anticipated to offer new treatment possibilities for peritoneal fibrosis in individuals with PD.

Circulating monocytes are drawn to the area of peritoneal injury following stimulation, where they undergo differentiation into either proinflammatory/cytotoxic (M1) or anti-inflammatory/wound healing (M2) macrophage subsets. Polarized macrophages secrete a plethora of cytokines/chemokines that contribute to peritoneal inflammatory injury, tissue repair, fibrosis, and angiogenesis. Additionally, these secreted factors further enhance the recruitment and polarization of macrophages.

Recent investigations have revealed that classical cytokines derived from peritoneal macrophages, such as IL-6 and IL-10, are pivotal in the pathogenesis of peritoneal inflammatory damage and fibrosis through intricate signaling pathways. In particular, IL-6, mainly produced by M1 macrophages, is identified as a key pro-inflammatory factor in the peritoneal cavity of patients receiving PD (27). In an inflammatory milieu driven by TGF-β1, heightened secretion of IL-6 can induce polarization of macrophages into a M2 phenotype, thereby contributing to the development of PD-induced peritoneal fibrosis (88). Yang et al. (89) showed that the stimulation of the JAK/STAT3 signaling pathway by IL-6 along with soluble IL-6 receptor (sIL-6R) can increase VEGF levels in human peritoneal mesothelial cells (HPMCs), thereby promoting peritoneal neovascularization. Furthermore, stimulation of HPMCs with the IL-6/sIL-6R complex induces the EMT process through the transcriptional activator 3 (STAT3) pathway (90). In mouse models, intraperitoneal injection of high-glucose dialysate triggers phosphorylated activation of STAT3, resulting in macrophage infiltration, peritoneal fibrosis, and angiogenesis. Blocking IL-6/sIL-6R signaling can prevent these alterations in the peritoneum. Additionally, levels of IL-6, VEGF, and angiopoietin-2 are elevated in PD effluents from PD patients (90). In contrast, IL-10 secreted by M2 macrophages is a versatile cytokine known for its strong anti-inflammatory effects (91). Growing evidence suggests that IL-10 can significantly suppress the production of several pro-inflammatory mediators, such as TNF-α, IL-1, and IL-6, under diverse pathological conditions (92). Furthermore, research has shown that IL-10 can effectively slow down the fibrosis process in various organs and tissues, including the heart, lungs, liver, and kidneys (93–97). Previous investigations have confirmed that peritoneal IL-10 may originate from tissue resident macrophages and exert regulatory effects on antigen-presenting cell recruitment, as well as inflammatory cell infiltration (98). Onishi et al. (99) validated a significant reduction in fibrous peritoneal thickening in rats overexpressing IL-10 with peritoneal fibrosis induced by methylacetalized (MGO). Additionally, overexpression of IL-10 markedly inhibits macrophage infiltration, along with the expression of TNF-a, IL-1β, IL-6, TGF-β1, Snail transcription factor gene (Snail), and MMP2 genes, while also suppressing mesenchymal cells proliferation. Consequently, peritoneal fibrosis is significantly alleviated.

Chemokines are essential in the context of autoimmune diseases, inflammation, and tissue fibrosis, positioning them as a central focus for both researchers and clinical treatments. Within this group of chemokines, the C-C motif chemokine ligand (CCL) family, particularly CCL1, CCL2, CCL17, CCL18, CCL22, and CCL24, are closely associated with macrophage polarization and contribute to induction of inflammatory and fibrotic damage. MCP-1/CCL2 is a well-known monocyte chemokine produced by M1 macrophages that facilitates the recruitment of monocyte-derived macrophages into injured tissues while promoting local inflammatory responses (100). Clinical evidence suggests that MCP-1/CCL2 could serve as a biomarker for predicting renal fibrosis and deterioration in function (101, 102). Furthermore, animal experimental studies have utilized MCP-1/CCL2 as a therapeutic target to improve preclinical kidney disease outcomes (103–105). Following polarization, M2 macrophages are capable of producing elevated amounts of IL-10, TGF-β, CCL1, CCL17, CCL18, CCL22, and CCL24. Their primary functions encompass anti-inflammatory responses, tissue regeneration and repair processes, angiogenesis promotion, as well as immune regulation (106). CCL17 is a ligand for the chemokine receptor type 4 (CCR4) in the C-C chemokine family that was initially found to be highly expressed in the thymus and act as a chemoattractant for T cells (107). M2 macrophages are capable of secreting CCL17, which activates fibroblasts, lymphocytes, and macrophages through a signaling pathway involving interaction with CCR4 (108, 109). In a mouse model of peritoneal fibrosis induced by sodium hypochlorite exposure (16), a notable rise in the expression levels of chemokines CCL17 and CCL22 was observed in peritoneal macrophages two days after the injury. This upregulation further stimulated collagen production along with fibroblast migration. Notably, administration of an anti-CCL17 antibody resulted in a substantial reduction in peritoneal myoblast infiltration, macrophage accumulation, and fibrotic changes. Similarly, AMAC-1/CCL18 is a chemokine specific to M2 macrophages that is also known as a lung and activation regulatory chemokine. In PD patients, elevated levels of CCL18 in effluents are linked to peritoneal dysfunction and fibrosis. This suggests that peritoneal M2 macrophages may play a role in the development of peritoneal fibrosis by facilitating fibroblast proliferation and enhancing CCL18 production (67). A different study validated that elevated levels of CCL18 were found in the effluents from patients undergoing long-term PD, which was associated with a compromised peritoneal transport status and the length of time on PD (110). Consequently, CCL, a chemokine produced by macrophages, is essential in triggering peritoneal inflammation, promoting angiogenesis, and stimulating fibroblast proliferation, as well as the subsequent development of long-term PD-induced peritoneal fibrosis.

Proteases are enzymes that catalyze the hydrolysis of proteins, breaking them down into smaller peptides or amino acids. Protein kinases, on the other hand, are enzymes that catalyze protein phosphorylation and regulate the final modification of proteins. Proteases and protein kinases are both vital in numerous cellular functions, including the degradation and restoration of proteins, modulation of cell signaling pathways, activation of enzyme precursors, and control of apoptosis. Recruitment, polarization, and secretion of macrophages require the participation of various signaling proteins. Therefore, proteases and protein kinases are either present or absent depending on their specific functions. This section will review the roles of and mechanisms by which proteases and protein kinases regulate macrophages during PD-induced peritoneal fibrosis.

MMPs are calcium- and zinc-dependent proteolytic enzymes that can be secreted by macrophages (111). The main role of MMPs is to break down the extracellular matrix (ECM), which is essential for processes such as cellular proliferation, growth, differentiation, migration, and communication between cells (112). Recent studies indicate that the expression of MMP-12 specifically in peritoneal macrophages from rat models with continuous exposure to glucose peritoneal dialysate. This finding suggests that PD-induced peritoneal injury involves increased expression of MMP-12 in peritoneal macrophages, underscoring the possible critical role of MMP-12 in the repair mechanisms related to peritoneal fibrosis (66). Research has demonstrated that various MMPs play a role in fibrosis following tissue and organ injury. For instance, the secretion of MMP2 and MMP9 by macrophages can promote pulmonary fibrosis in cases of idiopathic interstitial pneumonia (113). However, limited studies have been conducted on the involvement of macrophage-secreted MMPs in peritoneal dialysis-associated peritoneal fibrosis. Therefore, further investigations are warranted to elucidate the role of MMPs in macrophage-mediated regulation of peritoneal fibrosis during PD.

PKCs constitute a group of serine/threonine protein kinases, with several members widely expressed across different cells and tissues and play crucial roles in cellular function and multiple signal transduction (114). Studies have shown that PKCs serve as important signaling proteins that regulate the inflammatory cytokine response in peritoneal resident macrophages (115, 116). In a long-term mouse model of PD, upregulation and activation of peritoneal PKCα were observed, along with macrophages infiltration, EMT of peritoneal mesothelial cells, neovascularization, peritoneal fibrosis, and decreased ultrafiltration capacity (115). Administration of a PKCα blocker or gene deficiency can ameliorate the pathological changes in the peritoneum significantly by decreasing the levels of pro-inflammatory, pro-fibrotic, and pro-angiogenic mediators. In cell experiments, both PKCα blockers and PKCα deficiency inhibited MCP-1 release from mouse peritoneal mesothelial cells induced by PD while improving TGF-β1-induced EMT (115). Similarly, PKCβ expression can be observed in peritoneal macrophages of primary mice, and its upregulation is significantly induced in a high-glucose environment (70). In vivo, prolonged exposure to PD fluid containing high levels of glucose can lead to upregulation of peritoneal PKCβ in mice, resulting in fibrosis and neovascularization. In PKCβ gene knockout mice, all pathological alterations were significantly worsened when compared to wild-type mice. The main molecular mechanism is probably associated with the shift of peritoneal macrophages towards the pro-inflammatory M1 phenotype due to PKCβ deletion and the upregulation of PKCα in peritoneal mesial cells of mice. Furthermore, studies have also confirmed that PKCβ is involved in the M1/M2 polarization process of human peritoneal macrophages (70). In summary, these studies emphasize the importance of PKCs as an important molecular mediator of peritoneal macrophages during peritoneal fibrosis.

Transcriptional expression and gene activity are significantly influenced by transcription factors and epigenetic modifications (117, 118). Increasing evidence indicates that these factors and modifications play a role in regulating the expression and activation of cytokines and signaling molecules linked to peritoneal fibrosis (119). In the context of peritonitis, NF-κB and STAT3 become activated, leading to the production of multiple proinflammatory cytokines/chemokines such as IL-6, MCP-1, TNF-α, and IL-1β (120–124). MCP1, along with other chemokines, can induce macrophage aggregation in the peritoneum, leading to the secretion of TGF-β, connective tissue growth factor (CTGF), VEGF, and MMPs, thereby promoting the progression of peritoneal fibrosis (125). Ding and his team (126) created peritoneal fibrosis in mice by injecting high glucose dialysate (HG-PDF) intraperitoneally, which led to the phosphorylation of STAT3 and an influx of macrophages into the peritoneal cavity. The inhibitor sgi-201 targeting STAT3 effectively suppresses hyperglycemia-induced peritoneal fibrosis by inhibiting angiogenesis, macrophage infiltration, and HIF-1α expression.

Enhanced zeste homolog 2 (EZH2), a histone lysine methyltransferase, is capable of catalyzing the trimethylation of histone H3 at lysine 27 (H3K27me3) and can facilitate transcriptional silencing of numerous genes, such as E-cadherin (127). Activation may also be regulated through direct methylation of certain intracellular signaling molecules, including STAT3 (128). Liu et al. (129) discovered that EZH2 was abundantly expressed in peritoneal tissue of patients suffering from PD-associated peritonitis and in dialysis effluents from individuals undergoing long-term PD. They also confirmed a positive relationship between EZH2 expression and levels of TGF-β1, VEGF, and IL-6. Similarly, increased levels of EZH2 were noted in mouse peritoneum models induced by chlorhexidine gluconate (CG) or hyperglycemic peritoneal dialysate. Moreover, inhibition therapy targeting EZH2 in both models alleviated peritoneal fibrosis and suppressed the activation of various pro-fibrotic signaling pathways, such as TGF-β1/Smad3, Notch1, EGFR, and Src, as well as phosphorylation events involving STAT3 and NF-κB. Additionally, infiltration and angiogenesis processes involving injured peritoneal lymphocytes and macrophages were reduced (129).

Histone acetylation is a post-translational modification mechanism, and the histone deacetylase (HDAC) family being crucial in modulating various physiological and pathological activities associated with acetylation (130). HDAC1, a member of class I histone acetyltransferases, has been shown to play a role in peritoneal fibrosis. It has the ability to stimulate the expression of marker genes related to MMT that are extracted from the effluent of patients receiving PD (130). Another subtype of the HDAC family, HDAC6, primarily located in the cytoplasm, affects both histone and non-histone acetylation. The expression levels of HDAC6 increase in the peritoneal cavity and dialysis fluids of individuals receiving PD. This increase shows a positive correlation with the expression of TGF-β1, IL-6, and VEGF. Inhibiting HDAC6 can suppress IL-6/STAT3 and Wnt1/β-catenin signaling, leading to a decrease in VEGF production and PD-induced angiogenesis (131). Clearly, HDAC6 is crucial in IL-6-induced peritoneal EMT, along with the proliferation and migration of mesothelial cells in the peritoneum (132). Selective inhibition of HDAC6 significantly reduces CG-induced peritoneal fibrosis progression by limiting EMT and extracellular matrix protein deposition. Research conducted both in vivo and in vitro has indicated that blocking HDAC6 significantly attenuates M2 macrophage polarization in a dose-dependently manner by inhibiting TGF-β/Smad, IL4/STAT6, and PI3K/AKT signaling (133). Therefore, targeting HDAC6 holds promise for treating peritoneal fibrosis.

Disruptor of telomeric silencing 1-like (DOT1L) is a specialized histone methyltransferase that facilitates the methylation of lysine 79 on histone H3 in mammals and is associated with tissue and organ fibrosis in many diseases (134–136). Liu et al. (137) discovered notable elevation in DOT1L expression within fibrotic peritoneal tissues from patients undergoing long-term PD, as well as in mice models. Inhibiting DOT1L can effectively reduce the transdifferentiation of mesothelial cells and phenotypic differentiation of macrophages into M2 macrophages, thereby alleviating peritoneal fibrosis. Mechanistically, DOT1L primarily participates in protein tyrosine kinase binding processes and contributes to the structural composition of the peritoneal ECM. Studies have revealed that intracellular DOT1L guides H3K79me2 upregulation for EGFR expression in mesothelial cells and and the activation of JAK3 in macrophages, while extracellular DOT1L interacts with EGFR and JAK3 to sustain activated signaling. In conclusion, DOT1L promotes the expression and activation of tyrosine kinases, specifically EGFR in mesothelial cells and JAK3 in macrophages, driving cell differentiation towards a pro-fibrotic phenotype, ultimately leading to peritoneal fibrosis. Therefore, targeting DOT1L may offer new opportunities for clinical drug development against dialysis-associated peritoneal fibrosis.

Long non-coding RNAs (lncRNAs) refer to a category of RNA molecules that are longer than 200 nucleotides and do not code for proteins. They play key roles in regulating various intracellular processes, including inflammation, proliferation, and fibrosis (138). A microarray expression profiling analysis revealed differential expression of 232 lncRNAs in fibrotic peritonea (139). Specifically, expression of AK142426 was found to be upregulated. Jiang et al. (140) observed significant upregulation of AK142426 in PD effluents from mouse models with PD-induced peritoneal fibrosis. Subsequent investigations indicated that PD treatment led to the polarization of M2 macrophages and inflammation within the PD fluid. Encouragingly, the silencing of AK142426 inhibited M2 macrophage polarization and inflammation while alleviating peritoneal fibrosis in vivo. Furthermore, it was discovered that AK142426 can enhance expression and activation of c-Jun through its interaction with the c-Jun protein. Overexpression of c-Jun was shown to partially reverse the inhibitory effects of sh-AK142426 on M2 macrophage activation. These studies confirm that AK142426 promotes peritoneal M2 macrophage polarization and contributes to peritoneal fibrosis by upregulating c-Jun, highlighting its potential as a potential therapeutic target for individuals affected by PD.

A growing body of studies have confirmed that transcriptional and epigenetic mechanisms are indispensable for programmed macrophage aggregation, polarization, and activation of cytokine expression. Regulation of pro-fibrotic gene expression is essential for the progression of PD-induced peritoneal fibrosis, and a deeper understanding of the transcriptional and epigenetic mechanisms that govern macrophage behavior may lead to significant advancements in preventing and treating peritoneal fibrosis. However, additional research is still required to elucidate specific mechanisms and explore potential treatment possibilities.

The activation of NLRP3, a sensor protein for inflammasomes, triggers the assembly of oligomeric complexes that include apoptosis-associated speck-like protein (ASC) and caspase-1, collectively known as the “inflammasome.” The NLRP3 inflammasome drives caspase-1 activation by facilitating proteolytic cleavage of procaspase-1 and aiding in the transformation of the IL-1β precursor into its active variant. This process ultimately results in tissue inflammation and damage (141). Hautem et al. (142) indicated that NLRP3 inflammasomes are involved in peritoneal transport function decline and changes in peritoneal morphology during PD-associated peritonitis. In a mouse model of MGO-induced peritoneal fibrosis associated with PD, Takahashi et al. discovered that mice lacking NLRP3, ASC, and interleukin-1β (IL-1β) exhibited markedly decreased levels of inflammation-related proteins induced by PD, as well as decreased peritoneal fibrosis (143). The absence of ASC resulted in lower levels of inflammatory and fibrotic factors, as well as a reduction in macrophage infiltration. Additionally, the lack of ASC prevented the formation of MGO-induced hemorrhagic ascites, reduced fibrin deposition, and decreased the upregulation of plasminogen activator inhibitor-1. These findings suggest that endothelial NLRP3 inflammasomes participate in PD-associated peritoneal inflammation and fibrosis, providing novel perspectives on the pathogenesis of the disease.

Mesenchymal stem cells (MSCs) have strong immunomodulatory properties and can be readily isolated and expanded in vitro (144, 145). In recent years, there has been extensive research on the potential for MSCs to contribute to tissue and organ repair, as well as treat neurodegenerative diseases (146). Adipose-derived mesenchymal stem cells (ADSCs), a source of MSCs, have demonstrated immunomodulatory and anti-fibrotic effects in peritoneal fibrosis (147, 148). Yang et al. (88) investigated the therapeutic impacts of ADSCs and bone marrow-derived mesenchymal stem cells (BM-MSCs) in rat models suffering from peritoneal fibrosis induced by PD. They found that ADSCs exhibited a more significant therapeutic effect on peritoneal fibrosis than BM-MSCs. Furthermore, they confirmed a positive correlation between this therapeutic effect and polarization of M2 macrophages. Additionally, in vitro studies demonstrated that MSCs were exposed to an inflammatory environment characterized by the presence of TGF-β1, leading to the release of IL-6 and subsequent polarization of macrophages into the M2 phenotype. Ultimately, it is concluded that ADSCs can exert an anti-peritoneal fibrosis role by regulating peritoneal macrophage polarization. Given its abundant availability and ease of acquisition, ADSCs hold considerable promise for future applications.

Prolonged exposure to elevated glucose levels is well acknowledged as a major factor leading to peritoneal fibrosis due to pathological damage in PD (43). Cell-specific sodium-dependent glucose transporters (SGLTs) possess unique glucose sensing properties and serve as the main pathway for glucose uptake by mammalian cells (149). Research has shown that SGLT1 is expressed on the apical membrane of human PMCs (150). Recent investigations have confirmed the coexistence of SGLT1 and SGLT2 in rat peritonea (151). Balzer et al. (152) applied the selective SGLT2 inhibitor dagliazin to treat mouse model of peritoneal fibrosis triggered by high glucose from PD solution. They observed significant reductions in TGF-β concentrations in PD effluents, peritoneal thickening, fibrosis, and microvascular density after dagliazin treatment, leading to improved ultrafiltration. In vitro experiments revealed that dagliazin promoted M2 macrophage polarization while reducing cytokine release induced by high sugar levels in human and mouse peritoneal mesoepithelial cells. In summary, through regulation of macrophage polarization, dagliazin can ameliorate structural and functional damage associated with hyperglycemic PD.

Omega-3 fatty acids, a category of polyunsaturated fatty acid, have long been recognized for their abilities to promote cardiovascular health and reduce the risk of certain chronic diseases (153). One study revealed that dialysis patients exhibited significantly lower levels of omega-3 fatty acids, leading to an increased cardiovascular risk in those with chronic kidney disease (154). Liu et al. (69) showed that prolonged intravenous delivery of omega-3 fatty acids in PD rats effectively suppressed the expression of activation-related proteins (i.e., Erg2 and IRF4) in peritoneal M2 macrophages, whereas no notable changes were seen in the levels of activation-related proteins (i.e., CD38 and IRF5) in M1 macrophages. Furthermore, omega-3 fatty acids were found to significantly decrease the levels of fibrosis-related factors such as α-SMA, TGF-β1, and VEGF, as well as ALK5 proteins, thereby ameliorating peritoneal fibrosis.

Tubastatin A (TA) acts as a selective inhibitor of HDAC6. Liu et al. (133) discovered that TA effectively inhibits the polarization of M2 macrophages, suppresses the expression of MMP2 and MMP-9, and reduces EMT, as well as ECM, protein deposition in peritoneal mesoepithelial cells by blocking the TGF-b/Smad3, PI3K/AKT, STAT3, and STAT6 pathways. Consequently, TA significantly hinders the progression of peritoneal fibrosis. In vitro studies indicated that both IL-4 and HG-PDF promote M2 macrophage polarization by increasing the expression of CD163 and arginase-1. However, However, TA can inhibit HDAC6 activity in a dose-dependent manner, effectively reversing M2 macrophage polarization by downregulating TGF-b/Smad, IL4/STAT6, and PI3K/AKT signaling. To summarize, blocking HDAC6 with TA may ameliorate CG-induced peritoneal fibrosis progression by abolishing M2 macrophage polarization.

Jiang et al. (140) performed a study examining the impact of lncRNA AK142426 on peritoneal fibrosis and observed significant upregulation of AK142426 in the effusions of PD mice. Knocking down AK142426 was found to inhibit PD-induced polarization of M2 macrophages and inflammation, thereby alleviating peritoneal fibrosis. Furthermore, AK142426 was found to enhance expression and activation of c-Jun by interacting with c-Jun protein. Overexpression of c-Jun partially counteracted the suppressive effects of sh-AK142426 on M2 macrophage activation and inflammation. These findings confirm that AK142426 facilitates polarization of peritoneal M2 macrophages and contributes to peritoneal fibrosis via upregulation of c-Jun, highlighting its potential as a therapeutic target for patients suffering from peritoneal fibrosis.

Hepatocyte growth factor (HGF) is a growth factor derived from mesenchymal cells that has various effects on target cells (163). Studies have demonstrated significantly higher HGF concentrations in dialysate from patients with ultrafiltration failure (164). According to Tanoue et al. (157), HGF can notably decrease the quantity of peritoneal macrophages and markers associated with M1/M2 macrophages, including CD86, CD206, and CD163 in mice with methylglyoxal-induced peritoneal fibrosis. It also reduces the levels of pro-inflammatory cytokines TGF-β, TNF-α, and IL-1β. Furthermore, HGF can markedly decrease peritoneal membrane thickness and inhibit type I/III collagen expression, as well as α-SMA levels. In another study, macrophages were employed as vehicles to intravenously express and deliver the HGF gene to mice with peritoneal fibrosis induced by chlorhexidine gluconate. This approach led to significant reductions in α-SMA/TGF-β-positive cells within the peritoneum. Additionally, transplantation of these modified macrophages resulted in reduced intersubcutaneous thickening, along with decreased type III collagen expression, while maintaining ultrafiltration function (161).

New treatment strategies for peritoneal fibrosis, in addition to inhibiting aggregation and polarization of M2 macrophages, have been reported that target M1 macrophages, resulting in reductions in peritoneal fibrosis. Vervloet et al. (159) observed that, compared to standard lactic acid, bicarbonate/lactic acid buffer solution treatment resulted in a greater percentage of pro-inflammatory M1 macrophages within the pro-fibrotic M2 subgroup in PD mice. Liu et al. (158) showed that the autophagy inhibitor 3-MA markedly decreased infiltration of CD68-positive peritoneal macrophages, reversed EMT, and effectively prevented peritoneal fibrosis in rats. Administration of 3-deazaneplanocin A (3-DZNeP) in mouse models of CG- or HG-PDF-induced peritoneal fibrosis has been shown to mitigate peritoneal injury by reducing CD68+ macrophage invasion and angiogenesis through the inhibition of EZH2 methylation activity. Additionally, 3-DZNeP inhibits activation of multiple pro-fibrotic signaling pathways, thereby ameliorating peritoneal fibrosis (129). One study showed that overexpression of IL-10 significantly reduced infiltration of CD68+ peritoneal macrophages and thickening of the fibrous peritoneum in rats, resulting in notable relief from peritoneal fibrosis (99).

Besides M1 and M2 macrophages, non-categorized macrophages, including F4/80+ and ED1+ macrophages have been the subject of several other studies related to peritoneal fibrosis. In the CG-induced mouse model of peritoneal fibrosis, there was an accumulation of CD11b^intF4/80^int inflammatory macrophages (InfMϕs), while injection of anti-CCL17 antibodies significantly reduced InfMϕs, myofibroblasts, and peritoneal fibrosis in mice (16). Recent studies have indicated that astragalus extract can inhibit recruitment and activation of F4/80-positive mononuclear/macrophage cells in PD rat models, ultimately alleviating peritoneal fibrosis (155). Mitochondrial acid-5 (MA-5), an indole-3-acetic acid derivative, is a newly discovered drug that targets mitochondria. Torigoe et al. (156) showed that MA-5 treatment may improve peritoneal fibrosis by inhibiting F4/80-positive macrophages and oxidative stress, which in turn helps to restore mitochondrial function. Shushakova et al. (115) used the PKC inhibitor Go6976 or a PKCα gene defect to block the biological activity of PKCα in PD mice, resulting in alleviation of F4/80-positive macrophage invasion, peritoneal fibrosis, and neovascularization. In mice suffering from peritoneal fibrosis induced by MGO, administration of ligagliptin, which is a dipeptidyl peptidase-4 (DPP-4) inhibitor, blocked the infiltration of F4/80-positive macrophages and collagen deposition while improving peritoneal function (160). Competitive inhibitors targeting aldosterone mainly bind competitively to mannose receptors. Hao et al. (162) found that spironolactone treatment in rat models induced by PD dialysate and LPS reduced infiltration of ED-1-positive macrophages in rat peritoneal tissue, as well as decreased inflammation and fibrosis.

To conclude, the existing literature indicates that macrophages are essential in hindering the treatment of peritoneal fibrosis caused by PD. Some therapeutic studies have directly shown that amelioration of peritoneal fibrosis can be achieved through regulating macrophage polarization, while other reports have only observed a reduction in fibrotic macrophage infiltration accompanying the improvement of peritoneal fibrosis. Additionally, research has demonstrated that peritoneal macrophages undergo polarization into various phenotypes at different stages of peritoneal dialysis-induced injury. The literature reports reveal significant in vivo variability and variations in modeling time among the animal models employed to investigate peritoneal dialysis injury. According to research reports, the duration required for modeling therapeutic strategies targeting M1 macrophages or F4/80 positive macrophages typically does not exceed three weeks; however, establishing animal models for therapies primarily directed at M2 macrophages generally necessitates a longer timeframe. However, it remains uncertain whether inhibiting phenotypic changes in fibrotic macrophages contributes to a reduction in peritoneal fibrosis. Many studies investigating the molecular mechanism underlying macrophage-mediated peritoneal fibrosis have not explored the direct impact of cytokines on macrophages, while some recent drug studies on peritoneal fibrosis have failed to consider the polarization of macrophages. Consequently, future investigations into pharmacological interventions aimed at inhibiting peritoneal fibrosis through the regulation of peritoneal macrophages should prioritize the selection of appropriate methodologies and timelines for animal model development. Additionally, there is a pressing need for further research to focus on therapeutic agents that directly modulate macrophage polarization in order to enhance outcomes related to peritoneal fibrosis.