Department of Ophthalmology of Shanghai Tenth's People Hospital, Laboratory of Clinical Visual Science of Tongji Eye Institute, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, China; Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai, China.
Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China.
Exp Eye Res. 2021 Mar;204:108448. doi: 10.1016/j.exer.2021.108448. Epub 2021 Jan 20.
Photoreceptor (PR) dysfunction or death is the key pathological change in retinal degeneration (RD). The death of PRs might be due to a primary change in PRs themselves or secondary to the dysfunction of the retinal pigment epithelium (RPE). Poly(ADP-ribose) polymerase (PARP) was reported to be involved in primary PR death, but whether it plays a role in PR death secondary to RPE dysfunction has not been determined. To clarify this question and develop a new therapeutic approach, we studied the changes in PAR/PARP in the RCS rat, a RD model, and tested the effect of PARP intervention when given alone or in combination with RPE cell transplantation. The results showed that poly(ADP-ribosyl)ation of proteins was increased in PRs undergoing secondary death in RCS rats, and this result was confirmed by the observation of similar changes in sodium iodate (SI)-induced secondary RD in SD rats. The increase in PAR/PARP was highly associated with increased apoptotic PRs and decreased visual function, as represented by lowered b-wave amplitudes on electroretinogram (ERG). Then, as we expected, when the RCS rats were treated with subretinal injection of the PARP inhibitor PJ34, the RD process was delayed. Furthermore, when PJ34 was given simultaneously with subretinal ARPE-19 cell transplantation, the therapeutic effects were significantly improved and lasted longer than those of ARPE-19 or PJ34 treatment alone. These results provide a potential new approach for treating RD.
光感受器（PR）功能障碍或死亡是视网膜变性（RD）的关键病理变化。PR 的死亡可能是由于 PR 本身的原发性变化，或继发于视网膜色素上皮（RPE）的功能障碍。多聚（ADP-核糖）聚合酶（PARP）被报道参与原发性 PR 死亡，但它是否在 RPE 功能障碍引起的 PR 死亡中起作用尚未确定。为了阐明这个问题并开发新的治疗方法，我们研究了 RCS 大鼠（一种 RD 模型）中 PAR/PARP 的变化，并测试了单独给予或与 RPE 细胞移植联合给予 PARP 干预的效果。结果表明，在 RCS 大鼠的继发性 PR 死亡中，PR 中的蛋白多聚（ADP-核糖）化增加，这一结果通过在 SD 大鼠的碘酸钠（SI）诱导的继发性 RD 中观察到类似的变化得到了证实。PAR/PARP 的增加与凋亡性 PR 增加和视觉功能下降高度相关，表现为视网膜电图（ERG）上 b 波振幅降低。然后，正如我们所预期的，当用 PARP 抑制剂 PJ34 对 RCS 大鼠进行视网膜下注射治疗时，RD 过程被延迟。此外，当 PJ34 与视网膜下 ARPE-19 细胞移植同时给予时，治疗效果显著改善且持续时间长于 ARPE-19 或 PJ34 单独治疗。这些结果为治疗 RD 提供了一种新的潜在方法。
