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

Taito Miyake,Norihiko Sakai,Akira Tamai,Kengo Furuichi,Souichi Nakagawa ,Kōichi Sato ,Megumi Oda ,Yasutaka Kamikawa,Miho Shimizu,Yuta Yamamura,Yukiko Shinozaki ,Taro Miyagawa,Akihiro Sagara,Akinori Hara,Tadashi Toyama,Hajime Ogura ,Shinji Kitajima,Yasunori Iwata,Shuichi Kaneko,Takashi Wada

doi:10.1038/s41598-020-71230-4

Taito Miyake, Norihiko Sakai + Show 18 more

Open Access

https://doi.org/10.1038/s41598-020-71230-4

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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, ColIα1 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 ColIα1 mRNA expression induced by TGF-β1 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.

Highlights

Peritoneal fibrosis (PF) is a severe complication of peritoneal dialysis, but there are few effective therapies for it
To investigate whether peritoneal mesothelial cells (PMCs) were a source of myofibroblasts, we evaluated the number and distribution of Wilms tumor 1 (Wt1) and α-smooth muscle actin (α-SMA) dual positive cells during PF induced by chlorhexidine gluconate (CG) challenges
To further confirm the involvement of autophagy in mice model of PF treated with trehalose, we investigated the expression of LC3 in peritoneum during fibrosis by using LC3-green fluorescent protein (GFP) transgenic mice treated with chloroquine as previously reported[27]

Summary

Introduction

Peritoneal fibrosis (PF) is a severe complication of peritoneal dialysis, but there are few effective therapies for it. Trehalose (α-d-glucopyranosyl α-d-glucopyranoside) is a non-reducing disaccharide that consists of two 1,1-linked α-glucose monosaccharides This sugar is present in a wide variety of organisms including plants, bacteria, yeast, fungi, insects, and invertebrates. Recent studies have revealed a new biological effect of trehalose as an autophagy inducer, and it can be considered to be a hopeful candidate as a therapeutic agent for neurodegenerative diseases through the enhancement of unnecessary protein d egradation[21,22,23]. There are few reports concerning the therapeutic effects of trehalose by inducing autophagy on fibrotic diseases. We found that trehalose promoted Snail[1] degradation through induction of autophagy, thereby inhibiting MMT in response to TGF-β1, which could be a possible molecular mechanism. The current study suggests that trehalose could provide a beneficial therapeutic strategy to inhibit PF through the attenuation of MMT in PD patients

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