Gao Xiuhua, Li Yonghua, Wang Hongxia, Li Chuanbao, Ding Jianguang
Department of Ophthalmology, Jining Medical University Affiliated Hospital, Jining City, Shandong Province, China.
Acta Ophthalmol. 2017 Dec;95(8):e746-e750. doi: 10.1111/aos.13096. Epub 2016 Jun 11.
Recent studies demonstrate that pro-inflammatory cytokines (PICs, i.e. IL-1β, IL-6 and TNF-α) in retinal tissues are likely involved in the development of diabetic retinopathy (DR). In this report, we particularly examined contributions of hypoxia inducible factor subtype 1α (HIF-1α) to the expression of PICs and their receptors in diabetic retina.
Streptozotocin (STZ) was systemically injected to induce hyperglycaemia in rats. ELISA and Western blot analysis were employed to determine the levels of HIF-1α and PICs as well as PIC receptors in retinal tissues of control rats and STZ rats.
The levels of retinal HIF-1α were significantly increased in STZ rats 4-10 weeks after induction of hyperglycaemia as compared with control animals. With increasing HIF-1α retinal PICs including IL-1β, IL-6 and TNF-α, their respective receptors, namely IL-1R, IL-6R and TNFR1, were also elevated in STZ rats. Moreover, inhibition of HIF-1α by injection of 2-methoxyestradiol (2-MET) significantly decreased the amplified expression IL-6, TNF-α, IL-6R and TNFR1 in diabetic retina, but did not modify IL-1β pathway. In addition, we examined protein expression of Caspase-3 indicating cell apoptosis in the retina of STZ rats after infusing 2-MET, demonstrating that 2-MET attenuated an increase in Caspase-3 evoked by STZ.
Hypoxia inducible factor subtype 1α (HIF-1α) activated in diabetic retina is likely to play a role in regulating pathophysiological process via IL-6 and TNF-α mechanism. This has pharmacological implications to target specific HIF-1α, IL-6 and TNF-α signalling pathway for dysfunction and vulnerability related to DR.
近期研究表明，视网膜组织中的促炎细胞因子（PICs，即白细胞介素-1β、白细胞介素-6和肿瘤坏死因子-α）可能参与糖尿病视网膜病变（DR）的发生发展。在本报告中，我们特别研究了缺氧诱导因子1α（HIF-1α）亚型对糖尿病视网膜中PICs及其受体表达的影响。
全身注射链脲佐菌素（STZ）诱导大鼠高血糖。采用酶联免疫吸附测定（ELISA）和蛋白质免疫印迹分析来测定对照大鼠和STZ大鼠视网膜组织中HIF-1α、PICs以及PIC受体的水平。
与对照动物相比，高血糖诱导4至10周后，STZ大鼠视网膜中HIF-1α水平显著升高。随着视网膜中HIF-1α水平升高，STZ大鼠中的PICs（包括白细胞介素-1β、白细胞介素-6和肿瘤坏死因子-α）及其各自的受体，即白细胞介素-1受体（IL-1R）、白细胞介素-6受体（IL-6R）和肿瘤坏死因子受体1（TNFR1）也升高。此外，注射2-甲氧基雌二醇（2-MET）抑制HIF-1α可显著降低糖尿病视网膜中白细胞介素-6、肿瘤坏死因子-α、白细胞介素-6受体和肿瘤坏死因子受体1的扩增表达，但未改变白细胞介素-1β信号通路。此外，我们检测了注入2-MET后STZ大鼠视网膜中表明细胞凋亡的半胱天冬酶-3（Caspase-3）的蛋白表达，证明2-MET减弱了STZ诱导的Caspase-3的增加。
糖尿病视网膜中激活的缺氧诱导因子1α（HIF-1α）亚型可能通过白细胞介素-6和肿瘤坏死因子-α机制在调节病理生理过程中发挥作用。这对于针对与DR相关的功能障碍和易损性的特定HIF-1α、白细胞介素-6和肿瘤坏死因子-α信号通路具有药理学意义。
