Autophagy in peritoneal fibrosis

Abstract

Peritoneal dialysis (PD) is a widely accepted renal replacement therapy for patients with end-stage renal disease (ESRD). Morphological and functional changes occur in the peritoneal membranes (PMs) of patients undergoing long-term PD. Peritoneal fibrosis (PF) is a common PD-related complication that ultimately leads to PM injury and peritoneal ultrafiltration failure. Autophagy is a cellular process of "self-eating" wherein damaged organelles, protein aggregates, and pathogenic microbes are degraded to maintain intracellular environment homeostasis and cell survival. Growing evidence shows that autophagy is involved in fibrosis progression, including renal fibrosis and hepatic fibrosis, in various organs. Multiple risk factors, including high-glucose peritoneal dialysis solution (HGPDS), stimulate the activation of autophagy, which participates in PF progression, in human peritoneal mesothelial cells (HPMCs). Nevertheless, the underlying roles and mechanisms of autophagy in PF progression remain unclear. In this review, we discuss the key roles and potential mechanisms of autophagy in PF to offer novel perspectives on future therapy strategies for PF and their limitations.

Keywords: autophagy; human peritoneal mesothelial cells; peritoneal dialysis; peritoneal dialysis-related peritonitis; peritoneal fibrosis.

FIGURE 1

Effect of autophagy in peritoneal fibrosis. HGPDS contributes to MMT, inflammation and angiogenesis in peritoneal mesothelial cells, eventually cause PF. Some studies suggest that activation of autophagy reduces PF, whereas some evidences demonstrate that autophagy promotes PF. RAPA: rapamycin, RSV: resveratrol, MCL: micheliolide, HGPDS: high-glucose peritoneal dialysis solution, 3-MA: 3-methyladenine, PI3K: phosphatidylinositide 3-kinases, AMPK: AMP-activated protein kinase, mTOR: mammalian target of rapamycin, EGFR: epidermal growth factor receptor, ERK1/2: extracellular signal-regulated kinase 1/2, TGF-β: transforming growth factor-β, NLRP3: nod-like receptor 3, IL-1β: interleukin-1β, STAT3: signal transducer and activator of transcription 3, NF-κB: nuclear factor kappa-B, MMT: mesothelial-mesenchymal transition.

FIGURE 2

Effect of autophagy in PD-related peritonitis. Infectious factors lead to infection-related peritonitis via NF-κB/IL-6 pathway. In addition, under long-term stimulation of HGPDS, HPMCs suffer from non-infectious peritonitis by NLRP3/IL-1β pathway. However, these processes are blocked by the activation of autophagy. LPS: lipopolysaccharide, TLR4: toll like receptor 4, IL-6: interleukin-6, JNK: c-Jun N-terminal kinase, HSP72: heat shock protein 72, p38 MAPK: p38 mitogen activated protein kinases, JAK: Janus kinase.