Angiogenic Role of Mesothelium-Derived Chemokine CXCL1 During Unfavorable Peritoneal Tissue Remodeling in Patients Receiving Peritoneal Dialysis as Renal Replacement Therapy

Abstract

Peritoneal dialysis (PD) is a valuable ‘home treatment’ option, even more so during the ongoing Coronavirus pandemic. However, the long-term use of PD is limited by unfavourable tissue remodelling in the peritoneal membrane, which is associated with inflammation-induced angiogenesis. This appears to be driven primarily through vascular endothelial growth factor (VEGF), while the involvement of other angiogenic signaling pathways is still poorly understood. Here, we have identified the crucial contribution of mesothelial cell-derived angiogenic CXC chemokine ligand 1 (CXCL1) to peritoneal angiogenesis in PD. CXCL1 expression and peritoneal microvessel density were analysed in biopsies obtained by the International Peritoneal Biobank (NCT01893710 at www.clinicaltrials.gov), comparing 13 children with end-stage kidney disease before initiating PD to 43 children on chronic PD. The angiogenic potential of mesothelial cell-derived CXCL1 was assessed in vitro by measuring endothelial tube formation of human microvascular endothelial cells (HMECs) treated with conditioned medium from human peritoneal mesothelial cells (HPMCs) stimulated to release CXCL1 by treatment with either recombinant IL-17 or PD effluent. We found that the capillary density in the human peritoneum correlated with local CXCL1 expression. Both CXCL1 expression and microvessel density were higher in PD patients than in the age-matched patients prior to initiation of PD. Exposure of HMECs to recombinant CXCL1 or conditioned medium from IL-17-stimulated HPMCs resulted in increased endothelial tube formation, while selective inhibition of mesothelial CXCL1 production by specific antibodies or through silencing of relevant transcription factors abolished the proangiogenic effect of HPMC-conditioned medium. In conclusion, peritoneal mesothelium-derived CXCL1 promotes endothelial tube formation in vitro and associates with peritoneal microvessel density in uremic patients undergoing PD, thus providing novel targets for therapeutic intervention to prolong PD therapy.

Novel Aspects of the Immune Response Involved in the Peritoneal Damage in Chronic Kidney Disease Patients under Dialysis

“…Peritoneal mesothelium-derived chemokines have been recently proposed as potential therapeutic targets. In this sense, CXCL1 induced in MCs in response to IL-17 exposure displays angiogenic activity and can subsequently control the vascular remodeling in dialyzed peritoneum [ 103 ]. The observation of PD patients exhibiting high CXCL1 expression and subsequent density of microvessels opens to new intervening prospective acting to preserve long-term PM integrity and function.…”

“…It is well established, that peritoneal MCs when entering replicative senescence in vitro, secrete large amounts of proangiogenic (VEGF, CXCL1), proinflammatory (IL-6, IL-8, MCP-1/CCL2) and the profibrotic factors TGF-β and connective tissue growth factor (CTGF/CCN2), precisely known as the SASP components ( Figure 2 ) [ 116 ]. Different preclinical studies have demonstrated that these components of the SASP can significantly contribute to adverse peritoneal remodeling during PD by promoting MMT and angiogenesis [ 46 , 103 , 117 , 118 ].…”

Mechanisms of Peritoneal Mesothelial Cells in Peritoneal Adhesion

“…During PA formation, the production of inflammatory mediators regulates the ECM [ 43 ]. CXCL1 may be an important pro-angiogenic agent [ 67 ]. Catar et al showed that CXCL1 secreted by PMCs directly promotes human microvascular endothelial tube formation [ 67 ], and VEGF accelerates the PA process by participating in angiogenesis [ 68 , 69 ].…”

“…CXCL1 may be an important pro-angiogenic agent [ 67 ]. Catar et al showed that CXCL1 secreted by PMCs directly promotes human microvascular endothelial tube formation [ 67 ], and VEGF accelerates the PA process by participating in angiogenesis [ 68 , 69 ]. CXCL1 can also upregulate the expression of PAI-1 and promote fibrin deposition [ 3 ].…”

Systematic review to compare the outcomes associated with the modalities of expanded hemodialysis (HDx) versus high‐flux hemodialysis and/or hemodiafiltration (HDF) in patients with end‐stage kidney disease (ESKD)

“…Dialysis is the most frequently used renal replacement therapy (RRT) for end-stage kidney disease (ESKD) patients. It is estimated that almost 90% of these patients undergo hemodialysis (HD), with the remainder undergoing peritoneal dialysis, 1 although this value can vary between countries/regions, 2 for example, in Mexico where up to 70% of patients receive PD 3 and in Hong-Kong, which has a PD-first policy. 4,5 Conventional HD involves solute diffusion and limited ultrafiltration (weight loss for fluid control and internal filtration) across a high-flux membrane embedded in a hollow-fiber dialyser for 4 h per session.…”