Eye Institute, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, 430060, Hubei, China.
Eye Institute, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, 430060, Hubei, China; Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, 430071, Hubei, China.
Exp Eye Res. 2021 Sep;210:108728. doi: 10.1016/j.exer.2021.108728. Epub 2021 Aug 12.
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.
Magnetic microbeads 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.
The mRNA expression levels of Bmp4 and its downstream BMPRIa, small mothers against decapentaplegic 1 (Smad1), 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.
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.
骨形态发生蛋白 4（BMP4）信号的激活可促进急性损伤后视网膜神经节细胞（RGC）的存活。类 Chordin 蛋白 1（CHRDL1）是一种内源性 BMP 拮抗剂。在本研究中，我们研究了 CHRDL1 是否参与了青光眼小鼠模型中的 BMP4 信号转导和 RGC 变性的调节。
将磁性微珠注入眼前房以诱导小鼠模型中的实验性青光眼。设计了一种重组腺相关病毒（rAAV）系统，用于在小鼠视网膜中过表达 BMP4 或 CHRDL1。通过免疫组织化学和苏木精-伊红（HE）染色来识别视网膜形态的变化。通过视网膜电图（ERG）记录评估视觉功能的变化。
青光眼视网膜中 Bmp4 及其下游 BMPRIa、小 Smads 1（Smad1）的 mRNA 表达水平均显著上调。与 beads+AAV-EGFP 组相比，beads+AAV-BMP4 组的 RGC 存活显著增加，而 beads+AAV-CHRDL1 组的 RGC 存活显著减少。在体外视网膜外植体培养中也观察到了类似的结果。与这些发现一致的是，过表达 BMP4 可恢复 ERG 中的明视负反应（PhNR），这表明 RGC 功能，而 a 波和 b 波反应不受影响。CHRLD1 的激活抑制了 Smad1/5/8 的磷酸化并加重了 RGC 损伤。在 beads+AAV-BMP4 组中，神经胶质纤维酸性蛋白（GFAP）的表达显著降低。
BMP4 在实验性青光眼模型中促进了 RGC 的存活和视觉功能。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神经胶质细胞激活有关。我们的研究表明，BMP4 和 CHRLD1 可能成为青光眼的治疗靶点。
