Abstract
Accumulation of extracellular matrix (ECM) proteins in trabecular meshwork (TM), which leads to increased outflow resistance of aqueous humor and consequently high intraocular pressure, is a major cause of primary open-angle glaucoma (POAG). According to our preliminary research, the RapGAP protein superfamily member, signal-induced proliferation-associated 1-like 1 protein (SIPA1L1), which is involved in tissue fibrosis, may have an impact on POAG by influencing ECM metabolism of TM. This study aims to confirm these findings and identify effects and cellular mechanisms of SIPA1L1 on ECM changes and phagocytosis in human TM (HTM) cells. Our results showed that the expression of SIPA1L1 in HTM cells was significantly increased by TGF-β2 treatment in label-free quantitative proteomics. The aqueous humor and TM cell concentration of SIPA1L1 in POAG patients was higher than that of control. In HTM cells, TGF-β2 increased expression of SIPA1L1 along with accumulation of ECM, RhoA, and p-cofilin 1. The effects of TGF-β2 were reduced by si-SIPA1L1. TGF-β2 decreased HTM cell phagocytosis by polymerizing cytoskeletal actin filaments, while si-SIPA1L1 increased phagocytosis by disassembling actin filaments. Simultaneously, overexpressing SIPA1L1 alone exhibited comparable effects to that of TGF-β2. Our studies demonstrate that SIPA1L1 not only promotes the production of ECM, but also inhibits its removal by reducing phagocytosis. Targeting SIPA1L1 degradation may become a significant therapy for POAG.
Authors
Chenyu Xu, Jiahong Wei, Dan Song, Siyu Zhao, Mingmin Hou, Yuchen Fan, Li Guo, Hao Sun, Tao Guo
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