High dose expression of heme oxigenase-1 induces retinal degeneration through ER stress-related DDIT3

作者：Huirong Li, Bo Liu, Lili Lian, Jiajia Zhou, Shengjin Xiang, Yifan Zhai, Yu Chen, Xiaoyin Ma, Wencan Wu, Ling Hou · 发表于：Molecular Neurodegeneration · 年份：2021 · DOI：10.1186/s13024-021-00437-4 · 被引用次数：45 · 研究领域：Heme Oxygenase-1 and Carbon Monoxide、Retinal Diseases and Treatments、Endoplasmic Reticulum Stress and Disease

BACKGROUND: Oxidative stress is a common cause of neurodegeneration and plays a central role in retinal degenerative diseases. Heme oxygenase-1 (HMOX1) is a redox-regulated enzyme that is induced in neurodegenerative diseases and acts against oxidative stress but can also promote cell death, a phenomenon that is still unexplained in molecular terms. Here, we test whether HMOX1 has opposing effects during retinal degeneration and investigate the molecular mechanisms behind its pro-apoptotic role. METHODS: Basal and induced levels of HMOX1 in retinas are examined during light-induced retinal degeneration in mice. Light damage-independent HMOX1 induction at two different expression levels is achieved by intraocular injection of different doses of an adeno-associated virus vector expressing HMOX1. Activation of Müller glial cells, retinal morphology and photoreceptor cell death are examined using hematoxylin-eosin staining, TUNEL assays, immunostaining and retinal function are evaluated with electroretinograms. Downstream gene expression of HMOX1 is analyzed by RNA-seq, qPCR examination and western blotting. The role of one of these genes, the pro-apoptotic DNA damage inducible transcript 3 (Ddit3), is analyzed in a line of knockout mice. RESULTS: Light-induced retinal degeneration leads to photoreceptor degeneration and concomitant HMOX1 induction. HMOX1 expression at low levels before light exposure prevents photoreceptor degeneration but expression at high levels directly indu...