Abstract
Intraperitoneal inflammation is the most important determinant of peritoneal fibrosis in patients with long-term peritoneal dialysis (PD). Spliced x-box binding protein-1 (XBP1s), a major proximal effector of unfolded protein response (UPR) signaling, plays an indispensable role in inflammation. Our study demonstrated that the inflammatory factor interleukin-1β (IL-1β) dose- and time-dependently induced XBP1s upregulation and interleukin-6 (IL-6) secretion, as well as the expression of the fibrotic marker fibronectin. However, these effects were prevented by the IRE1 endonuclease inhibitor STF083010 since it time-dependently reduced IL-1β-induced Xbp1 mRNA splicing, XBP1s protein expression, inflammatory factor IL-6 secretion and the expression of the fibrotic marker fibronectin in human peritoneal mesothelial cells (HPMCs). The overexpression and knockdown of XBP1s in HPMCs had a similar effect on fibronectin expression. In a rat model of peritoneal inflammation, STF083010 significantly attenuated chlorhexidine digluconate-induced XBP1s and α-smooth muscle actin expression, as well as fibrotic tissue proliferation, in the peritoneum. Our results suggest that XBP1s is a strong pathogenic factor that mediates inflammation-induced peritoneal fibrosis in peritoneal dialysis.
Highlights
Intraperitoneal inflammation is the most important determinant of peritoneal fibrosis in patients with long-term peritoneal dialysis (PD)
To mimic inflammation in peritoneal dialysis, we treated human peritoneal mesothelial cells (HPMCs) with the inflammatory factor IL-1β to identify whether XBP1s is involved in this inflammatory process
IL-1β significantly induced XBP1s protein expression (Fig. 1C) in HPMCs. These results suggest that XBP1s is likely involved in the inflammatory process in HPMCs in peritoneal dialysis
Summary
Intraperitoneal inflammation is the most important determinant of peritoneal fibrosis in patients with long-term peritoneal dialysis (PD). Several factors contribute to peritoneal inflammation during long-term PD These factors include (1) the inflammatory status of chronic kidney disease as a result of a reduction in the renal clearance of cytokines, fluid overload, immunological dysfunction and infectious comorbidity[4], (2) long-term exposure of the peritoneal membrane to unphysiological dialytic solutions with high glucose and low pH5, (3) PD-related peritonitis[6], (4) uremia-induced inflammation in the peritoneum[7], and (5) protein energy wasting[8]. These factors are usually related to one other and eventually lead to peritoneal fibrosis. Gene XBP1s Sense Antisense IL-6 Sense Antisense IL-8 Sense Antisense TNFα Sense Antisense 18S RNA Sense Antisense
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