Du Lu, Peng Guang-Hua
Department of Ophthalmology, Chinese PLA General Hospital, Beijing, 100039, China.
Laboratory of Visual Cell Differentiation and Regulation, Basic Medical College, Zhengzhou University, 100 Science Ave, Zhengzhou, 450001, Henan, China.
Eye Vis (Lond). 2022 Jun 9;9(1):22. doi: 10.1186/s40662-022-00292-4.
It has been found that the extensive use of anticancer drugs containing DNA-alkylating agents not only target cancer cells but also cause retinal inflammation through toxic intermediates. Complement C3 (C3) is a core component of the complement activation pathway, and dysregulation of the complement pathway is involved in several retinal degenerative diseases. However, whether C3 plays a critical role in alkylation-induced retinal degeneration is unclear.
Following treatment with the alkylating agent methyl methane sulfonate (MMS), the C3 mRNA and protein level was measured, DNA damage and photoreceptor cell death were assessed in both wild-type (WT) C57BL/6J and C3 knockout (KO) mice.
We determined that complement pathway is activated following MMS treatment, and C3 knockout (KO) increased the rate of photoreceptor cell survival and preserved visual function. The mRNA levels of nuclear erythroid-related factor 2 (Nrf2) and related genes were higher after MMS application in C3 KO mice.
In summary, our study found that C3 KO promotes photoreceptor cell survival and activates the Nrf2 signaling pathway in the context of alkylation-induced retinal degeneration.
已发现广泛使用含DNA烷化剂的抗癌药物不仅作用于癌细胞，还会通过毒性中间体引发视网膜炎症。补体C3（C3）是补体激活途径的核心成分，补体途径失调与多种视网膜退行性疾病有关。然而，C3在烷化诱导的视网膜变性中是否起关键作用尚不清楚。
用烷化剂甲磺酸甲酯（MMS）处理后，检测野生型（WT）C57BL/6J小鼠和C3基因敲除（KO）小鼠的C3 mRNA和蛋白水平，评估DNA损伤和光感受器细胞死亡情况。
我们确定MMS处理后补体途径被激活，C3基因敲除（KO）提高了光感受器细胞的存活率并保留了视觉功能。在C3基因敲除小鼠中应用MMS后，核红细胞相关因子2（Nrf2）及其相关基因的mRNA水平更高。
总之，我们的研究发现，在烷化诱导的视网膜变性情况下，C3基因敲除可促进光感受器细胞存活并激活Nrf2信号通路。
