Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China.
Invest Ophthalmol Vis Sci. 2019 May 1;60(6):2072-2082. doi: 10.1167/iovs.19-26585.
Excessive accumulation of extracellular matrix (ECM) in the trabecular meshwork (TM) reduces aqueous humor outflow, which likely contributes to elevation of IOP in primary open-angle glaucoma (POAG). Salidroside, a phenolic glycoside isolated from Rhodiola rosea is reported to prevent profibrotic responses by inhibiting Smad signaling pathway activated by TGF-β in liver, lung, and kidney tissues. We tested if salidroside can (1) inhibit TGF-β2-induced ECM expression in cultured human TM cells, and (2) lower TGF-β2-induced ocular hypertension in the mouse.
Cultured human TM cells stimulated with 5 ng/mL TGF-β2 for 48 hours were treated with salidroside for 24 hours. The expressions of fibronectin (FN), collagen type IV (COL-IV), and laminin (LN) were evaluated by quantitative PCR, Western blot, and immunocytochemistry. BALB/cJ mice were injected intravitreally with an adenoviral vector encoding a bioactive mutant of TGF-β2 (Ad.hTGF-β2226/228) in one eye to induce ocular hypertension, with the uninjected contralateral or Ad.Empty-injected eyes serving as controls. Mice were treated with a daily intraperitoneal injection of 40 mg/kg salidroside. Conscious mouse IOP values were measured using a TonoLab rebound tonometer.
In cultured human TM cells, treatment with TGF-β2 increased expressions of FN, COL-IV, and LN, as assessed by quantitative PCR, Western blotting, and immunocytochemistry, all of which were significantly and completely ameliorated by 30 μM salidroside. Daily intraperitoneal injections of salidroside (40 mg/kg), starting either at day 0 (same day as Ad.hTGF-β2226/228 injection) or at day 14, significantly lowered TGF-β2-induced ocular hypertension in the mouse. In contrast, salidroside did not affect IOP of control eyes.
These results demonstrated that salidroside is capable of minimizing TGF-β2-induced ECM expression in cultured human TM cells. It also reduced TGF-β2-induced ocular hypertension in the mouse. These findings indicate that this phenolic glycoside may be useful as a novel treatment for POAG.
细胞外基质（ECM）在小梁网中的过度积累会减少房水流出，这可能导致原发性开角型青光眼（POAG）中的眼压升高。从红景天中分离出的酚糖苷红景天苷已被报道可通过抑制 TGF-β激活的 Smad 信号通路来预防肝、肺和肾组织中的成纤维反应。我们测试了红景天苷是否可以：（1）抑制 TGF-β2 诱导的培养人 TM 细胞中 ECM 的表达，和（2）降低 TGF-β2 诱导的小鼠眼内高压。
用 5ng/ml TGF-β2 刺激培养的人 TM 细胞 48 小时，用红景天苷处理 24 小时。通过定量 PCR、Western blot 和免疫细胞化学评估纤维连接蛋白（FN）、IV 型胶原（COL-IV）和层粘连蛋白（LN）的表达。将编码生物活性突变型 TGF-β2（Ad.hTGF-β2226/228）的腺病毒载体单侧玻璃体注射到 BALB/cJ 小鼠眼内，以诱导眼内高压，未注射的对侧眼或 Ad.Empty 注射眼作为对照。用每天腹腔注射 40mg/kg 红景天苷治疗小鼠。使用 TonoLab 回弹眼压计测量清醒小鼠的眼内压。
在培养的人 TM 细胞中，用 TGF-β2 处理后，FN、COL-IV 和 LN 的表达通过定量 PCR、Western blot 和免疫细胞化学评估均显著增加，所有这些均被 30μM 红景天苷完全改善。从第 0 天（与 Ad.hTGF-β2226/228 注射同日）或第 14 天开始，每天腹腔注射 40mg/kg 红景天苷可显著降低 TGF-β2 诱导的小鼠眼内高压。相比之下，红景天苷对对照眼的眼压没有影响。
这些结果表明，红景天苷能够最小化 TGF-β2 诱导的培养人 TM 细胞中 ECM 的表达。它还降低了 TGF-β2 诱导的小鼠眼内高压。这些发现表明，这种酚糖苷可能作为 POAG 的一种新的治疗方法有用。
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