MTA-SE Lendület "Momentum" Diabetes Research Group, Semmelweis University, 1083 Budapest, Hungary.
Pediatric Center, MTA Center of Excellence, Faculty of Medicine, Semmelweis University, 1083 Budapest, Hungary.
Int J Mol Sci. 2023 Jul 19;24(14):11646. doi: 10.3390/ijms241411646.
Primary open-angle glaucoma remains a global issue, lacking a definitive treatment. Increased intraocular pressure (IOP) is considered the primary risk factor of the disease and it can be caused by fibrotic-like changes in the trabecular meshwork (TM) such as increased tissue stiffness and outflow resistance. Previously, we demonstrated that the sigma-1 receptor (S1R) agonist fluvoxamine (FLU) has anti-fibrotic properties in the kidney and lung. In this study, the localization of the S1R in TM cells was determined, and the anti-fibrotic efficacy of FLU was examined in both mouse and human TM cells. Treatment with FLU reduced the F-actin rearrangement, inhibited cell proliferation and migration induced by the platelet-derived growth factor and decreased the levels of fibrotic proteins. The protective role of the S1R in fibrosis was confirmed by a more pronounced increase in alpha smooth muscle actin and F-actin bundle and clump formation in primary mouse S1R knockout TM cells. Furthermore, FLU demonstrated its protective effects by increasing the production of nitric oxide and facilitating the degradation of the extracellular matrix through the elevation of cathepsin K. These findings suggest that the S1R could be a novel target for the development of anti-fibrotic drugs and offer a new therapeutic approach for glaucoma.
原发性开角型青光眼仍是一个全球性问题，缺乏明确的治疗方法。眼内压（IOP）升高被认为是该病的主要危险因素，它可由小梁网（TM）的纤维样改变引起，如组织硬度增加和流出阻力增加。先前，我们证明了 sigma-1 受体（S1R）激动剂氟伏沙明（FLU）在肾脏和肺部具有抗纤维化特性。在这项研究中，确定了 S1R 在 TM 细胞中的定位，并在小鼠和人 TM 细胞中检查了 FLU 的抗纤维化效果。FLU 的治疗减少了 F-肌动蛋白的重排，抑制了血小板衍生生长因子诱导的细胞增殖和迁移，并降低了纤维化蛋白的水平。通过在原代小鼠 S1R 敲除 TM 细胞中更明显地增加α平滑肌肌动蛋白和 F-肌动蛋白束的形成和聚集，证实了 S1R 在纤维化中的保护作用。此外，FLU 通过增加一氧化氮的产生并通过升高组织蛋白酶 K 促进细胞外基质的降解来发挥其保护作用。这些发现表明，S1R 可能成为开发抗纤维化药物的新靶点，并为青光眼提供新的治疗方法。
