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

J Cell Mol Med. 2019 Oct;23(10):6872-6884. doi: 10.1111/jcmm.14571. Epub 2019 Aug 9.

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.

Keywords: ST2 blockade; peritoneal dialysis; peritoneal fibrosis; soluble ST2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • Epithelial-Mesenchymal Transition / drug effects
  • Epithelium / pathology
  • Female
  • Glucose / toxicity*
  • Humans
  • Interleukin-1 Receptor-Like 1 Protein / antagonists & inhibitors*
  • Interleukin-1 Receptor-Like 1 Protein / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Peritoneal Dialysis
  • Peritoneal Fibrosis / pathology*
  • Peritoneum / pathology
  • Proportional Hazards Models
  • Survival Analysis
  • Transforming Growth Factor beta / toxicity*

Substances

  • IL1RL1 protein, human
  • Interleukin-1 Receptor-Like 1 Protein
  • Transforming Growth Factor beta
  • Glucose