Targeting the ERK/NF-κB/Snail1 pathway as a potential therapeutic strategy to prevent the failure of peritoneal dialysis

Peritoneal dialysis is frequently used as an alternative to haemodialysis for the treatment of end-stage renal disease. The peritoneum acts in dialysis as a semipermeable membrane across which ultrafiltration and diffusion take place. Continual exposure to bio-incompatible solutions and episodes of peritonitis or haemoperitoneum damage the peritoneal membrane, which progressively undergoes fibrosis and angiogenesis, leading ultimately to ultrafiltration failure. Changes induced by prolonged inflammatory stimuli in peritoneal mesothelial cells are reminiscent of those occurring during epithelial-to-mesenchymal transition (EMT). Thus, the mechanistic regulation of EMT genesis in the peritoneal membrane is relevant from both basic and clinical perspectives. In our study, we reproduced EMT in vitro by treating primary mesothelial cells with effluent from patients undergoing peritoneal dialysis or by co-stimulation with transforming growth factor (TGF)-β1 and interleukin (IL)-1β. All of the aforementioned stimuli induced a genuine EMT, characterised by reduced E-cadherin and cytokeratin expression, cell scattering, and spindle-like morphology. We tried to identify the molecular mechanisms underlying this phenomenon and concluded that Snail1, induced by both ERK and NF-κB, is a master molecule that induces EMT in this experimental system. Interestingly, the blockage of ERK/NF-κB/Snail1 signalling in ex vivo cultured mesothelial cells from patients undergoing peritoneal dialysis reverted morphological and biochemical EMT in these cells. Modulation of the ERK/NF-κB/Snail1 activation pathway may thus provide a means of counteracting the progressive alteration of the peritoneal membrane and prolong the viability of peritoneal dialysis for the treatment of uremic patients.