Abstract
Purpose :
Lysophosphatidic acid (LPA) is a bioactive lipid mediator that is essential for a variety of cellular processes including proliferation, differentiation, transcription and survival. LPA signalling is dysregulated in many conditions such as cancer, atherosclerosis, and pulmonary and renal fibrosis. LPA is produced extracellularly by Autotaxin (ATX) and is degraded by three membrane bound lipid phosphate phosphatases (LPP 1-3). It acts via six G-protein coupled receptors on the cell surface (LPA1-6) to activate intracellular pathways. LPA enhances fibroblast proliferation, migration and contraction, and induces expression of pro-fibrotic mediators such as connective tissue growth factor. In glaucoma, there is disturbed extracellular matrix remodelling and fibrosis in the lamina cribrosa of the optic nerve head, and it is within this region that retinal ganglion cell axons degenerate. We wished to assess whether LPA signalling plays a role in mediating fibrosis in the lamina cribrosa in glaucoma.
Methods :
We cultured primary human lamina cribrosa cells from age-matched normal and glaucoma patient donors. Quantitative real time PCR was used to assess expression of gene targets within the LPA axis, as well as those involved in fibrosis. These included the LPA1-3 receptors, ATX, the LPPs, Collagen 1a1 (COL1A1), Fibronectin, and Alpha Smooth Muscle Actin (a-SMA).
Results :
Genes overexpressed in glaucoma lamina cribrosa cells included ATX, LPP3, LPA1 and LPA3 receptors. Expression of the fibrosis genes COL1A1, a-SMA and Fibronectin was also upregulated in glaucoma compared to normal lamina cribrosa cells.
Conclusions :
Our results show that the LPA signalling axis is altered in glaucoma. This suggests a role for the LPA axis in the fibrotic changes observed in the lamina cribrosa in glaucoma and may indicate a potential pharmacological target.
This is a 2021 ARVO Annual Meeting abstract.