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The Nrf2 activator MIND4‐17 protects retinal ganglion cells from high glucose‐induced oxidative injury
Author(s) -
Chen Nan,
Li Ya,
Huang Nan,
Yao Jin,
Luo WeiFeng,
Jiang Qin
Publication year - 2020
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.29619
Subject(s) - cytoprotection , keap1 , reactive oxygen species , small interfering rna , microbiology and biotechnology , oxidative stress , apoptosis , biology , gene silencing , oxidative phosphorylation , chemistry , biochemistry , transfection , transcription factor , gene
Diabetic retinopathy (DR) is a leading cause of acquired blindness among adults. High glucose (HG) induces oxidative injury and apoptosis in retinal ganglion cells (RGCs), serving as a primary pathological mechanism of DR. MIND4‐17 activates nuclear‐factor‐E2‐related factor 2 (Nrf2) signaling via modifying one cysteine (C151) residue of Kelch‐like ECH‐associated protein 1 (Keap1). The current study tested its effect in HG‐treated primary murine RGCs. We show that MIND4‐17 disrupted Keap1–Nrf2 association, leading to Nrf2 protein stabilization and nuclear translocation, causing subsequent expression of key Nrf2 target genes, including heme oxygenase‐1 and NAD(P)H quinone oxidoreductase 1. Functional studies showed that MIND4‐17 pretreatment significantly inhibited HG‐induced cytotoxicity and apoptosis in primary murine RGCs. Reactive oxygen species production and oxidative injury in HG‐treated murine RGCs were attenuated by MIND4‐17. Nrf2 silencing (by targeted small interfering RNA) or knockout (by CRISPR/Cas9 method) abolished MIND4‐17‐induced RGC cytoprotection against HG. Additionally, Keap1 knockout or silencing mimicked and abolished MIND4‐17‐induced activity in RGCs. In vivo, MIND4‐17 intravitreal injection activated Nrf2 signaling and attenuated retinal dysfunction by light damage in mice. We conclude that MIND4‐17 activates Nrf2 signaling to protect murine RGCs from HG‐induced oxidative injury.

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