Loss of JNK-Associated Leucine Zipper Protein Promotes Peritoneal Dialysis-Related Peritoneal Fibrosis

Abstract

<b><i>Background:</i></b> Peritoneal dialysis-related peritoneal fibrosis is the leading cause of peritoneal ultrafiltration failure. Multitude factors and pathological processes have been implicated in peritoneal fibrosis development and progression, whereas the intrinsic anti-fibrotic mechanism has rarely been explored. JNK-associated leucine zipper protein (JLP) has been recently found possessing powerful anti-fibrotic merits of overall antagonizing TGF-β-induced profibrotic effects. <b><i>Objectives:</i></b> We wondered whether JLP is expressed in the peritoneum, and if so, whether it exerts the anti-fibrotic effects similar to those in the kidney. <b><i>Method:</i></b> Here, we examined and confirmed JLP expression in peritoneum tissue of mice. Then, we established a peritoneal fibrosis model in <i>Jlp</i> wild-type and <i>Jlp</i> global deficient mice and observed the different effects of Jlp on peritoneal fibrosis progression. In vitro studies were performed on peritoneal mesothelial HMrSV5 cells with or without Jlp knockdown to investigate the underlying mechanism by which Jlp exerts anti-fibrotic effects. <b><i>Results:</i></b> We found that the expression of JLP decreased in a high-glucose peritoneal dialysis solution (HGPDS)-induced peritoneal fibrosis mouse model and in HGPDS-treated peritoneal mesothelial cell HMrSV5. JLP deletion exacerbated HGPDS-induced peritoneal fibrosis in peritoneal fibrosis mice, and knockdown of JLP resulted in an increased profibrotic response to HGPDS stimulation in HMrSV5 cells, which was associated with epithelial-to-mesenchymal transition, elevated autophagy, and apoptosis, as well as enhanced TGF-β1/Smad signaling activation. <b><i>Conclusions:</i></b> Our findings revealed a new anti-fibrotic factor of Jlp involved in peritoneal fibrosis induction and shed light on novel therapeutic targets in peritoneal ultrafiltration failure.

Current Insights into Cellular Determinants of Peritoneal Fibrosis in Peritoneal Dialysis: A Narrative Review

“…For example, JNK-associated leucine zipper protein (JLP) was found to have potent antifibrotic properties that counteract the profibrotic effects of TGF-β. In mice that experience peritoneal fibrosis due to dialysate induction of high glucose, there is a decrease in JLP expression, whereas JLP deletion induces the formation of peritoneal fibrosis associated with EMT, increased autophagy and apoptosis, and increased activation of TGF-β1/Smad signaling [ 22 ].…”