Blockade of Autophagy Prevents the Development and Progression of Peritoneal Fibrosis.

Yingfeng Shi,Xiaoyan Ma,Shougang Zhuang,Min Tao,Lunxian Tang,Na Liu,Yan Hu,Andong Qiu,Yi Wang

doi:10.3389/fphar.2021.724141

Yingfeng Shi, Xiaoyan Ma + Show 7 more

Open Access

https://doi.org/10.3389/fphar.2021.724141

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Abstract

Peritoneal fibrosis (PF) is a major cause of ultrafiltration failure in long-term peritoneal dialysis (PD) patients. Nevertheless, limited measures have been shown to be effective for the prevention and treatment of PF. Some views reveal that activation of autophagy ameliorates PF but others demonstrate that autophagy promotes PF. It is obvious that the role of autophagy in PF is controversial and further studies are needed. Here, we investigated the role of autophagy in rat models of PF and damaged cultured human peritoneal mesothelial cells (HPMCs). Autophagy was highly activated in fibrotic peritoneum from two PF rat models induced by 4.25% peritoneal dialysate fluid (PDF) and 0.1% chlorhexidine gluconate (CG). Blockade of autophagy with 3-MA effectively prevented PF in both models and reversed epithelial to mesenchymal transition (EMT) by down-regulating TGF-β/Smad3 signaling pathway and downstream nuclear transcription factors Slug and Snail. Treatment with 3-MA also inhibited activation of EGFR/ERK1/2 signaling pathway during PF. Moreover, 3-MA prominently decreased STAT3/NF-κB-mediated inflammatory response and macrophage infiltration, and prevented peritoneal angiogenesis through downregulation of β-catenin signal. In addition, TGF-β1 stimulation up-regulated autophagic activity as evidenced by the increased autophagosome in vitro. Exposure of HPMCs to TGF-β1 resulted in the induction of EMT and activation of TGF-β/Smad3, EGFR/ERK1/2 signaling pathways. Treatment with 3-MA blocked all these responses. In addition, delayed administration of 3-MA was effective in reducing EMT induced by TGF-β1. Taken together, our study indicated that autophagy might promote PF and 3-MA had anti-fibrosis effect in vivo and in vitro. These results suggest that autophagy could be a potential target on PF therapy for clinical patients with long-term PD.

Highlights

Peritoneal dialysis (PD) is a well-established alternative therapy for patients with end-stage renal disease (ESRD)
Our research group demonstrated for the first time that epidermal growth factor receptor (EGFR) and its downstream molecules participated in peritoneal fibrosis (PF), and inhibition of EGFR blocked the development and progression of mouse PF induced by chlorhexidine gluconate (CG) (Wang et al, 2016)
We examined the activation of autophagy in fibrotic peritoneum from two PF rat models injected with 4.25% peritoneal dialysate fluid (PDF) for 28 days and 0.1% CG for 21 days, and in transforming growth factor β1 (TGF-β1)-stimulated human peritoneal mesothelial cells (HPMCs)

Summary

Introduction

Peritoneal dialysis (PD) is a well-established alternative therapy for patients with end-stage renal disease (ESRD). Autophagy Inhibition Prevents Peritoneal Fibrosis promotes continuous exposure of the peritoneal membrane to bioincompatible dialysis solutions, which leads to the alteration of normal peritoneal membrane structure and loss of ultrafiltration function, eventually causes the progressive development of peritoneal fibrosis (PF) and forces patients to withdraw from PD (Krediet and Struijk, 2013; Zhou et al, 2016a; Krediet, 2018). Mounting evidence has demonstrated that transforming growth factor β1 (TGF-β1)-induced EMT is a pivotal process of progressive PF (Margetts et al, 2005). Except for TGF-β1/Smad signaling pathway, activation of epidermal growth factor receptor (EGFR) pathway is another important mechanism during PF progress. Our research group demonstrated for the first time that EGFR and its downstream molecules participated in PF, and inhibition of EGFR blocked the development and progression of mouse PF induced by chlorhexidine gluconate (CG) (Wang et al, 2016)

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