The Nrf2 activator MIND4-17 protects retinal ganglion cells from high glucose-induced oxidative injury |
| |
Authors: | Nan Chen Ya Li Nan Huang Jin Yao Wei-Feng Luo Qin Jiang |
| |
Institution: | 1. The Fourth School of Clinical Medicine, The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, Jiangsu, China;2. The Central Lab, North District, Suzhou Municipal Hospital Affiliated to Nanjing Medical University, Suzhou, Jiangsu, China;3. Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China |
| |
Abstract: | 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. |
| |
Keywords: | high glucose Nrf2 and MIND4-17 oxidative stress retinal ganglion cells |
|
|