PYGM downregulates necroptosis signaling to attenuate sodium iodate-induced RPE cell degeneration

Background: Age-related macular degeneration (AMD) causes incurable vision loss in elderly individuals, and there is currently only a rarely effective treatment for dry AMD. Necroptosis is attracting increasing attention in the context of AMD. This study aimed to elucidate the mechanisms underlying the induction of abnormal Necroptosis in AMD.

Methods: Sodium iodate (SI) was used to establish in vitro and in vivo retinal pigment epithelium cell (RPE) degeneration models and to simulate dry AMD-like conditions. Phenotypes and classic Necroptosis markers were identified. RNA-seq was performed on the retinas of RPE-degeneration mice and combined with the GSE29801 microarray data of human AMD retinal samples to identify the key genes regulating Necroptosis. Key genes were overexpressed both in vivo and in vitro to further validate their function in Necroptosis and RPE degeneration.

Results: Necroptosis phenotypes and the expression of the Necroptosis markers RIPK1, RIPK3, and MLKL were upregulated in both SI-treated ARPE-19 cells and the RPE layer of mice. Transcriptome data from SI-treated mice and patients with AMD revealed that the reduced expression of PYGM is implicated in the regulation of Necroptosis. PYGM overexpression in RPE cells and mouse retinas alleviated SI-induced RPE degeneration.

Conclusions: This study confirmed that PYGM attenuates Necroptosis in cellular and animal models resembling dry AMD, providing a new perspective on exploring novel AMD treatment targets.

Age-related macular degeneration; Necroptosis; PYGM.