ST2 blockade mitigates peritoneal fibrosis induced by TGF‐β and high glucose

Abstract

Peritoneal fibrosis (PF) is an intractable complication of peritoneal dialysis (PD) that leads to peritoneal membrane failure. This study investigated the role of suppression of tumorigenicity (ST)2 in PF using patient samples along with mouse and cell‐based models. Baseline dialysate soluble (s)ST2 level in patients measured 1 month after PD initiation was 2063.4 ± 2457.8 pg/mL; patients who switched to haemodialysis had elevated sST2 levels in peritoneal effluent (1576.2 ± 199.9 pg/mL, P = .03), which was associated with PD failure (P = .04). Baseline sST2 showed good performance in predicting PD failure (area under the receiver operating characteristic curve = 0.780, P = .001). In mice with chlorhexidine gluconate‐induced PF, ST2 was expressed in fibroblasts and mesothelial cells within submesothelial zones. In primary cultured human peritoneal mesothelial cells (HPMCs), transforming growth factor‐β treatment increased ST2, fibronectin, β‐galactosidase and Snail protein levels and decreased E‐cadherin level. Anti‐ST2 antibody administration reversed the up‐regulation of ST2 and fibronectin expression; it also reduced fibrosis induced by high glucose (100 mmol/L) in HPMCs. Thus, high ST2 level in dialysate is a marker for fibrosis and inflammation during peritoneal injury, and blocking ST2 may be an effective therapeutic strategy for renal preservation.

Loss of JNK-Associated Leucine Zipper Protein Promotes Peritoneal Dialysis-Related Peritoneal Fibrosis

“…TGF-β1 regulates cell physiology, proliferation, and differentiation and plays a critical role in the pathogenesis and development of various diseases [5]. Previous studies indicated that TGF-β1 is a novel profibrotic factor that enhances the expression of profibrotic genes through a novel signaling cascade [4, 5]. It has been reported that blocking the TGF-β1 signaling pathway could significantly attenuate angiogenesis and peritoneal fibrosis in PD mouse models [29].…”

“…PD-related peritoneal fibrosis is identical to EMT of peritoneal mesothelial cells, and the loss of peritoneal membrane function results in UF failure. PD solution induces peritoneal irritation, which promotes peritoneal mesothelial cells to translation into a mesenchymal phenotype, including the downregulation of epithelial markers such as E-cadherin and the upregulation of mesenchymal protein expression, such as N-cadherin, vimentin, and α-SMA, a process mediated by TGF-β1 [4]. EMT usually refers to a switch of E- to N-cadherin.…”

“…The pathogenesis of peritoneal fibrosis is an extremely complex process that involves multiple factors and cell events, including excessive activation of the transforming growth factor-β (TGF-β) signaling pathway, epithelial mesenchymal transition (EMT), apoptosis, dysregulation of autophagy, and inflammatory infiltration. TGF-β1 is a major profibrotic factor and the main molecule that causes the degeneration of peritoneal structure and function [4, 5]. TGF-β1 is recognized as the main subtype of fibrotic regulation [6] and a prototypical inducer of EMT [7].…”

Inflammatory chemokine ( C‐C motif) ligand 8 inhibition ameliorates peritoneal fibrosis

“…Effluent from clinically stable patients was obtained and immediately processed 18 . Bags were suspended for 3–4 h in an incubator at 37°C to allow the cells to settle at the bottom.…”

Saikosaponin D Inhibits Peritoneal Fibrosis in Rats With Renal Failure by Regulation of TGFβ1/ BMP7 / Gremlin1/ Smad Pathway

“…Wang et al, 2018b) (Morinelli et al, 2016). Currently, only a few treatments, such as metformin and tamoxifen, or genetic approaches such as gene knockout, have shown to inhibit EMT in vivo or in vitro in an effective way (Shin et al, 2017) (Chul et al, 2019) (Yan et al, 2018). Therefore, an urgent need remains for an effective clinical treatment of PD-associated peritoneal fibrosis.…”