Background: Peritoneal fibrosis is a serious complication of peritoneal dialysis, but the mechanisms by which it develops remain to be fully determined. Previous studies have shown that the lipid mediator lysophosphatidic acid (LPA), acting through one of its receptors, LPA1, stimulates peritoneal mesothelial cells (PMCs) to produce connective tissue growth factor . In this study, we investigated additional effects of LPA-LPA1 signaling on PMC biology, focusing on their migration and acquisition of a myofibroblast-like phenotype.
Methods: We isolated PMCs from wild-type (WT) and LPA 1 -deficient (LPA1KO) mice and determined their chemotaxis and expression of alpha smooth muscle actin ( α SMA), a marker of myofibroblast differentiation, induced by LPA.
Results: WT-PMCs migrated toward LPA in a dose-dependent manner, whereas LPA did not stimulate LPA1KO -PMC migration. The chemotactic activity of LPA on WT cells was completely inhibited by pertussis toxin, an inhibitor of the G αi class of G proteins. In addition to migration, w e found that LPA induced αSMA gene expression by PMCs, also in an LPA1-dependent manner, which were suppressed by the inhibition of G α 12/13 .
Conclusion: Our results suggest that LPA - LPA1 signaling contributes to the pathogenesis of peritoneal fibrosis by driving PMC migration and myofibroblast differentiation.