Tran Minh Ngoc, Medveczki Timea, Besztercei Balazs, Torok Gyorgy, Szabo Attila J, Gasull Xavier, Kovacs Illes, Fekete Andrea, Hodrea Judit
MTA-SE Lendület "Momentum" Diabetes Research Group, Semmelweis University, 1083 Budapest, Hungary.
Semmelweis University Pediatric Center, MTA Center of Excellence, 1083 Budapest, Hungary.
Life (Basel). 2023 Jul 19;13(7):1581. doi: 10.3390/life13071581.
The trabecular meshwork (TM) route is the principal outflow egress of the aqueous humor. Actin cytoskeletal remodeling in the TM and extracellular matrix (ECM) deposition increase TM stiffness, outflow resistance, and elevate intraocular pressure (IOP). These alterations are strongly linked to transforming growth factor-β2 (TGFβ2), a known profibrotic cytokine that is markedly elevated in the aqueous humor of glaucomatous eyes. Sigma-1 receptor (S1R) has been shown to have neuroprotective effects in the retina, but data are lacking about its role in the TM. In this study, we identified the presence of S1R in mouse TM tissue and investigated the effect of an S1R agonist fluvoxamine (FLU) on TGFβ2-induced human TM cells regarding cell proliferation; ECM-related functions, including F-actin reorganization; and the accumulation of ECM elements. TGFβ2 increased the proliferation, cytoskeletal remodeling, and protein levels of fibronectin, collagen type IV, and connective tissue growth factor, and decreased the level of matrix metalloproteinase-2. Most importantly, FLU reversed all these effects of TGFβ2, suggesting that S1R agonists could be potential candidates for preserving TM function and thus maintaining normal IOP.
小梁网（TM）途径是房水的主要流出通道。小梁网中的肌动蛋白细胞骨架重塑和细胞外基质（ECM）沉积会增加小梁网的硬度、流出阻力，并升高眼压（IOP）。这些改变与转化生长因子-β2（TGFβ2）密切相关，TGFβ2是一种已知的促纤维化细胞因子，在青光眼患者的房水中显著升高。西格玛-1受体（S1R）已被证明在视网膜中具有神经保护作用，但关于其在小梁网中的作用的数据尚缺乏。在本研究中，我们确定了小鼠小梁网组织中存在S1R，并研究了S1R激动剂氟伏沙明（FLU）对TGFβ2诱导的人小梁网细胞在细胞增殖、ECM相关功能（包括F-肌动蛋白重组）以及ECM成分积累方面的影响。TGFβ2增加了细胞增殖、细胞骨架重塑以及纤连蛋白、IV型胶原和结缔组织生长因子的蛋白水平，并降低了基质金属蛋白酶-2的水平。最重要的是，FLU逆转了TGFβ2的所有这些作用，表明S1R激动剂可能是保留小梁网功能从而维持正常眼压的潜在候选药物。
