Overexpression of BMP4 protects retinal ganglion cells in a mouse model of experimental glaucoma
Overexpression of BMP4 protects retinal ganglion cells in a mouse model of experimental glaucoma
复制标题
BMP4 过度表达可保护实验性青光眼小鼠模型中的视网膜神经节细胞
DOI：
10.1016/j.exer.2021.108728
复制
发表时间：
2021-08-14
影响因子：
3.4
通讯作者：
Shen, Yin
中科院分区：
文献类型：
--
作者：
Liu, Dongmei;Deng, Qinqin;Shen, Yin
目的：骨形态发生蛋白（BMP） 4信号的激活促进视网膜神经节细胞（RGC）在急性损伤后的存活。chorordinlike 1 （CHRDL1）是一种内源性BMP拮抗剂。在本研究中，我们在青光眼小鼠模型中研究CHRDL1是否参与BMP4信号传导和调控RGC变性。方法：采用眼内注射磁珠诱导实验性青光眼小鼠模型。设计了重组腺相关病毒（rAAV）系统，在小鼠视网膜中过表达BMP4或CHRDL1。采用免疫组织化学和苏木精-伊红（HE）染色检测视网膜形态学变化。视网膜电图（ERG）记录用于评估视觉功能的变化。结果：青光眼视网膜中Bmp4及其下游BMPRIa小母抗十肢截瘫1 (small mothers against decapentaplegic 1, Smadl) mRNA表达水平显著上调。与珠粒+ AAV-EGFP组相比，珠粒+ AAV-BMP4组的RGC生存期显著提高，珠粒+ AAV-CHRDL1组的RGC生存期显著降低。在视网膜离体培养中也观察到类似的结果。与这些发现一致的是，过度表达BMP4的小鼠ERG中显示RGC功能的photopic negative response （PhNR）反应得到恢复，而a波和b波反应则没有恢复。激活CHRLD1抑制Smad1/5/8磷酸化，加重RGC损伤。微珠+ AAV-BMP4组胶质原纤维酸性蛋白（GFAP）表达显著降低。结论：BMP4可促进实验性青光眼RGC存活，改善视功能。CHRDL1的激活通过抑制BMP4/Smad1/5/8通路加重了RGC变性。BMP4/ Smad1/5/8通路的机制可能与抑制胶质细胞活化有关。我们的研究提示BMP4和CHRLD1可能是青光眼的治疗靶点。
Purpose: Activation of bone morphogenetic protein (BMP) 4 signaling promotes the survival of retinal ganglion cell (RGC) after acute injury. Chordin-like 1 (CHRDL1) is an endogenous BMP antagonist. In this study, we researched whether CHRDL1 was involved in BMP4 signaling and regulation of RGC degeneration in a mouse model of glaucoma.Methods: Magnetic micmbeads were intracameral injected to induce experimental glaucoma in a mouse model. A recombinant adeno-associated virus (rAAV) system was designed for overexpression of BMP4 or CHRDL1 in mouse retina. Immunohistochemistry and hematoxylin-eosin (HE) stains were performed to identify changes in retinal morphology. Electroretinogram (ERG) recordings were used to assess changes in visual function.Results: The mRNA expression levels of Bmp4 and its downstream BMPRIa, small mothers against decapentaplegic 1 (Smadl), were significantly upregulated in retinas with glaucoma. RGC survival was significantly enhanced in the beads + AAV-BMP4 group and significantly reduced in the beads + AAV-CHRDL1 group, compared with the beads + AAV-EGFP group. Similar results were observed in retinal explant culture in vitro. Consistent with these findings, the photopic negative response (PhNR)responses in ERG, which indicate RGC function, were restored in mice overexpressing BMP4, whereas a-wave and b-wave responses were not. Activation of CHRLD1 inhibited Smad1/5/8 phosphorylation and exacerbated RGC damage. The expression of Glial fibrillary acidic protein (GFAP) was decreased significantly in beads + AAV-BMP4 group.Conclusions: BMP4 promoted RGC survival and visual function in an experimental glaucoma model. Activation of CHRDL1 exaggerated RGC degeneration by inhibiting the BMP4/Smad1/5/8 pathway. The mechanism of BMP4/ Smad1/5/8 pathway may be related to the inhibition of glial cell activation. Our studies suggested that BMP4 and CHRLD1 might serve as therapeutic targets in glaucoma.