Project title
Lysophosphatidic Acid 在腹膜纖維化的角色 (II)
Internal ID
NSC102-2314-B002-029
Principal Investigator
Start Date
August 1, 2013
End Date
July 31, 2014
Organizations
Partner Organizations
Role of Lysophosphatidic Acid in Peritoneal Fibrosis (II) = Lysophosphatidic acid 在腹膜纖維化的角色 (II)
Keywords
Ki16425
Lysophosphatidic acid
peritoneal dialysis
peritoneal fibrosis
Description
Long-term peritoneal dialysis (PD) is associated with alterations in the structure of peritoneal membrane resulted from unphysiological dialysate. The unique pathological finding is thickened submesothelial zone which composed with dense collagen deposition. The thickness of submesothelial zone increased with prolonged PD duration. The peritoneal fibrosis (PF) would lead to ultrafiltration failure and even catastrophic encapsulating peritoneal sclerosis (EPS). The definite pathogenesis remain unclear but several growth factors and inflammatory cytokines will be associated with PF. Lysophosphatidic acid (LPA) is present in the human blood and owns many functions. LPA is also constitutively produced by human peritoneal mesothelial cells. It can enhance wound repair and tissue development by promoting cell growth, proliferation, differentiation, motility, and survival. In addition, LPA is also associated with fibrosis through LPA1 receptor and the following connective tissue growth factors (CTGF) production. LPA can also upregulate inflammatory cytokines therefore induce transforming growth factor (TGF) secretion, and the following extracellular matrix production. This is the whole pathogenesis process of PF and LPA provide more upstream information prior to inflammatory cytokines secretion. In the first year, our results from in vitro cell level study, high glucose would enhance the secretion of LPA as well as CTGF and TGF-beta mRNA synthesis in human peritoneal mesothelial cell (HPMC). In addition, LPA could also enhance both the CTGF and TGF-beta as well as collagen I expression in HPMC. The Ki16425 suppressed the enhancing effects of both high glucose and LPA. The above results suggested that Ki16425 might be the therapeutic agents for peritoneal fibrosis. In addition, we also measure LPA levels in some PD patients’ peritoneal effluent. PET results were correlated with the LPA levels in the effluent. Form these results from in vitro and in vivo studies, we concluded a hypothesis that high glucose dialysate enhanced LPA secretion in peritoneal cavity therefore induced peritoneal fibrosis which resulted in high PET. In order to further investigate the mechanism between the LPA and peritoneal fibrosis, we will extend our study in the following years. In the second year, we will work on the signal pathway between LPA and collagen I with mRNA micro-array and collagen promoter assay. In addition, we will collect more PD effluent samples from PD patients during peritoneal equilibration test and peritonitis episode. These samples will measure LPA concentration as well as TGF beta, interleukin 6, hyaluronan, and CA 125. These factors will be analyzed with clinical characteristics. In the third year, the study will be continued into an in vivo rat dialysate infusion model. The secretion of LPA in the peritoneal cavity will be measured. The LPA1 expression on the peritoneum will be analyzed with qPCR and immunochemical stain. The fibrosis induced by the 4.25 % dialysate will be analyzed with microscopy and fibrogenic genes expression including CTGF, collagen I, and TGF-beta. We investigate this issue from the cell levels, in vivo animal model and extend to the patients’ phenotype. After completing these studies, the role of LPA in PD patients will be more clarified. The pathway between LPA and PF will also provide a therapeutic target for treating PF.