Trehalose ameliorates peritoneal fibrosis by promoting Snail degradation and inhibiting mesothelial-to-mesenchymal transition in mesothelial cells

Abstract

Peritoneal fibrosis (PF) is a severe complication of peritoneal dialysis, but there are few effective therapies for it. Recent studies have revealed a new biological function of trehalose as an autophagy inducer. Thus far, there are few reports regarding the therapeutic effects of trehalose on fibrotic diseases. Therefore, we examined whether trehalose has anti-fibrotic effects on PF. PF was induced by intraperitoneal injection of chlorhexidine gluconate (CG). CG challenges induced the increase of peritoneal thickness, ColIα 1 mRNA expression and hydroxyproline content, all of which were significantly attenuated by trehalose. In addition, CG challenges induced a marked peritoneal accumulation of α-SMA + myofibroblasts that was reduced by trehalose. The number of Wt1 + α-SMA + cells in the peritoneum increased following CG challenges, suggesting that a part of α-SMA + myofibroblasts were derived from peritoneal mesothelial cells (PMCs). The number of Wt1 + α-SMA + cells was also suppressed by trehalose. Additionally, trehalose attenuated the increase of α-SMA and ColIα 1 mRNA expression induced by TGF-β 1 through Snail protein degradation, which was dependent on autophagy in PMCs. These results suggest that trehalose might be a novel therapeutic agent for PF through the induction of autophagy and the suppression of mesothelial-to-mesenchymal transition in PMCs. Organ fibrosis is a common pathway that finally results in organ failure. Disease-related injuries are responsible for triggering fibrogenic responses. Fibrosis is a short-term adaptive response for wound healing, but prolonged injuries progress and lead to the overproduction of extracellular matrix (ECM). The dynamic deposition of ECM promotes progression to organ fibrosis and ultimately to organ failure 1. Peritoneal fibrosis (PF) is a serious complication for patients undergoing peritoneal dialysis (PD) 2 , which is a life-sustaining therapy for patients with end-stage renal disease worldwide, which accounts for 11% of the overall dialysis population 3. Dialysis solution is hyperosmotic and hyperglycemic, and can induce consecutive peritoneal injuries, thus inducing the progression of peritoneal fibrosis 4. The development of PF causes encapsulating peritoneal sclerosis, which is a lethal complication of PD and an important problem that makes long-term PD difficult 2,5,6. However, the precise molecular mechanisms for the development of PF need to be clarified to establish therapeutic strategies.

Blueberry Juice Attenuates Pulmonary Fibrosis via Blocking the TGF-β1/Smad Signaling Pathway

“…We detected 30 potential chemicals in BBJ by the method of LC/MS, which is consistent with previous studies ( Chen et al, 2010 ; Yang and Jiang, 2010 ). Importantly, trehalose, quercetin, rutin, ferulic acid, abscisic acid, and trolox were reported to relieve fibrosis by inhibiting TGF-β ( Galicia-Moreno et al, 2008 ; Bruzzone et al, 2012 ; Pan et al, 2014 ; Mu et al, 2018 ; Liu et al, 2019 ; Miyake et al, 2020 ). These phytochemicals were all found in BBJ and may have contributed to the anti-lung fibrosis function of BBJ.…”

Delayed Administration of Nintedanib Ameliorates Fibrosis Progression in CG-Induced Peritoneal Fibrosis Mouse Model

“…In response to many stimuli such as high glucose and inflammatory factors, PMCs can undergo EMT that is characterized by loss of cell adhesion, decreased expression of E-cadherin, and increased expression of α-SMA and β-vimentin [ 15 , 26 ]. Twist and Snail, the two major transcription factors, play a critical role in driving EMT process [ 9 , 27 ]. In this study, we found that delayed administration of nintedanib inhibited CG-stimulated upregulation of Snail or Twist, along with downregulation of β-vimentin, α-SMA, and retained E-cadherin expression.…”

Dihydroartemisinin Inhibits TGF-β-Induced Fibrosis in Human Tenon Fibroblasts via Inducing Autophagy

“…A previous study indicated that α-SMA plays an important role in fibrosis. 12 In addition, collagen I and survivin are known to be positively associated with the progression of fibrosis. 33 , 34 Consistent with these previous findings, in the present study, DHA inhibited the formation of HS via the inhibition of α-SMA, survivin and collagen I. Additionally, it has been reported that the activation of α-SMA promotes the epithelial-mesenchymal transition (EMT) process.…”

“…10 The aberrant occurrence of autophagy can lead to the dysfunction of cellular organelles. 11,12 On the other hand, autophagy protects organisms from inflammatory injuries via the modulation of the apoptotic cascade. 13 Recent studies have revealed that autophagy plays a crucial role in the formation of HS; [13][14][15] however, the association between DHA and cell autophagy in HS remains unclear.…”