Loosening of the mesothelial barrier as an early therapeutic target to preserve peritoneal function in peritoneal dialysis

Abstract

Phenotype transition of peritoneal mesothelial cells (MCs) including the epithelial-to-mesenchymal transition (EMT) is regarded as an early mechanism of peritoneal dysfunction and fibrosis in peritoneal dialysis (PD), producing proinflammatory and pro-fibrotic milieu in the intra-peritoneal cavity. Loosening of intercellular tight adhesion between adjacent MCs as an initial process of EMT creates the environment where mesothelium and submesothelial tissue are more vulnerable to the composition of bio-incompatible dialysates, reactive oxygen species, and inflammatory cytokines. In addition, down-regulation of epithelial cell markers such as E-cadherin facilitates de novo acquisition of mesenchymal phenotypes in MCs and production of extracellular matrices. Major mechanisms underlying the EMT of MCs include induction of oxidative stress, pro-inflammatory cytokines, endoplasmic reticulum stress and activation of the local renin-angiotensin system. Another mechanism of peritoneal EMT is mitigation of intrinsic defense mechanisms such as the peritoneal antioxidant system and anti-fibrotic peptide production in the peritoneal cavity. In addition to use of less bio-incompatible dialysates and optimum treatment of peritonitis in PD, therapies to prevent or alleviate peritoneal EMT have demonstrated a favorable effect on peritoneal function and structure, suggesting that EMT can be an early interventional target to preserve peritoneal integrity.

Mitochondrial Dysfunction Plays a Relevant Role in Pathophysiology of Peritoneal Membrane Damage Induced by Peritoneal Dialysis

“…Unfortunately, long-term exposure to these non-physiologic PD solutions, as well as to the peritoneal catheter, may lead to progressive peritoneal membrane injury resulting in PD technique failure and even mortality [ 4 ]. Mesothelial cells lining the peritoneal cavity represent the first line of contact with PD fluids, and appear to play an active role in the loss of integrity of the peritoneal membrane during PD therapy [ 5 , 6 , 7 , 8 ].…”

“…During EMT, mesothelial cells experience a decrease in the expression of epithelial markers, including E-cadherin, enhancing the expression of mesenchymal markers like fibronectin, collagen I or α-smooth muscle actin (α-SMA) [ 7 ]. As a consequence, cells acquire invasive capacities and reach the submesothelial stroma, where they produce extracellular matrix—but also inflammatory and angiogenic—factors, promoting peritoneal oxidative stress, inflammation and, finally, fibrosis, affecting peritoneal transport of water and solutes and resulting in ultrafiltration failure [ 6 , 12 ].…”

Effects of TGF-β1 Receptor Inhibitor GW788388 on the Epithelial to Mesenchymal Transition of Peritoneal Mesothelial Cells

“…The mortality of patients with encapsulating peritoneal sclerosis ranges between 26% and 58% [ 13 , 14 , 15 ]. These pathological changes were caused by bioincompatible dialysate, uremic condition, or peritonitis [ 2 , 10 , 11 ]. Treatment options include PD discontinuation, nutritional support, use of immunosuppressants, such as glucocorticosteroid, rapamycin, azathioprine, tamoxifen, and surgical treatment [ 8 ].…”

“…Fibrotic change in the peritoneal membrane can be caused by various conditions, such as exposure to uremia, high-glucose solutions, glucose-degradation products, or peritonitis. Transforming growth factor-beta 1 (TGF-β)-induced epithelial to mesenchymal transition (EMT) is an important pathway underlying the development of PF caused by various conditions [ 2 ]. Previous studies investigated the attenuation of TGF-β-induced EMT with various interventions with favorable results [ 1 , 3 , 4 ].…”

TGF-β1 Receptor Inhibitor SB525334 Attenuates the Epithelial to Mesenchymal Transition of Peritoneal Mesothelial Cells via the TGF-β1 Signaling Pathway

“…PD requires peritoneal dialysate within the peritoneal cavity for solute transport or water removal. Artificial peritoneal dialysate lacks biocompatibility, owing to factors such as high glucose, osmolarity, or glucose degradation products, which results in peritoneal membrane damage [2,3]. Repeated peritoneal membrane damage can lead to fibrosis and/or thickening of the peritoneal membrane.…”