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Extracellular superoxide dismutase (SOD3) regulates oxidative stress at the vitreoretinal interface.

ABSTRACT: Oxidative stress is a pathogenic feature in vitreoretinal disease. However, the ability of the inner retina to manage metabolic waste and oxidative stress is unknown. Proteomic analysis of antioxidants in the human vitreous, the extracellular matrix opposing the inner retina, identified superoxide dismutase-3 (SOD3) that localized to a unique matrix structure in the vitreous base and cortex. To determine the role of SOD3, Sod3-/- mice underwent histological and clinical phenotyping. Although the eyes were structurally normal, at the vitreoretinal interface Sod3-/- mice demonstrated higher levels of 3-nitrotyrosine, a key marker of oxidative stress. Pattern electroretinography also showed physiological signaling abnormalities within the inner retina. Vitreous biopsies and epiretinal membranes collected from patients with diabetic vitreoretinopathy (DVR) and a mouse model of DVR showed significantly higher levels of nitrates and/or 3-nitrotyrosine oxidative stress biomarkers suggestive of SOD3 dysfunction. This study analyzes the molecular pathways that regulate oxidative stress in human vitreous substructures. The absence or dysregulation of the SOD3 antioxidant at the vitreous base and cortex results in increased oxidative stress and tissue damage to the inner retina, which may underlie DVR pathogenesis and other vitreoretinal diseases.

SUBMITTER: Wert KJ

PROVIDER: S-EPMC6233711 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Extracellular superoxide dismutase (SOD3) regulates oxidative stress at the vitreoretinal interface.

Wert Katherine J KJ Velez Gabriel G Cross Madeline R MR Wagner Brett A BA Teoh-Fitzgerald Melissa L ML Buettner Garry R GR McAnany J Jason JJ Olivier Alicia A Tsang Stephen H SH Harper Matthew M MM Domann Frederick E FE Bassuk Alexander G AG Mahajan Vinit B VB

Free radical biology & medicine 20180622

Oxidative stress is a pathogenic feature in vitreoretinal disease. However, the ability of the inner retina to manage metabolic waste and oxidative stress is unknown. Proteomic analysis of antioxidants in the human vitreous, the extracellular matrix opposing the inner retina, identified superoxide dismutase-3 (SOD3) that localized to a unique matrix structure in the vitreous base and cortex. To determine the role of SOD3, Sod3<sup>-/-</sup> mice underwent histological and clinical phenotyping. A ...[more]

PMID: 29940351

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Project description:Chronic hypoxic stress induces epigenetic modifications mainly DNA methylation in cardiac fibroblasts, inactivating tumor suppressor genes (RASSF1A) and activating kinases (ERK1/2) leading to fibroblast proliferation and cardiac fibrosis. The Ras/ERK signaling pathway is an intracellular signal transduction critically involved in fibroblast proliferation. RASSF1A functions through its effect on downstream ERK1/2. The antioxidant enzyme, extracellular superoxide dismutase (EC-SOD), decreases oxidative stress from chronic hypoxia, but its effects on these epigenetic changes have not been fully explored. To test our hypothesis, we used an in-vitro model: wild-type C57B6 male mice (WT) and transgenic males with an extra copy of human hEC-SOD (TG). The studied animals were housed in hypoxia (10% O2) for 21 days. The right ventricular tissue was studied for cardiac fibrosis markers using RT-PCR and Western blot analyses. Primary C57BL6 mouse cardiac fibroblast tissue culture was used to study the in-vitro model, the downstream effects of RASSF-1 expression and methylation, and its relation to ERK1/2. Our findings showed a significant increase in cardiac fibrosis markers: Collagen 1, alpha smooth muscle actin (ASMA), and SNAIL, in the WT hypoxic animals as compared to the TG hypoxic group (p < 0.05). The expression of DNA methylation enzymes (DNMT 1&3b) was significantly increased in the WT hypoxic mice as compared to the hypoxic TG mice (p < 0.001). RASSF1A expression was significantly lower and ERK1/2 was significantly higher in hypoxia WT compared to the hypoxic TG group (p < 0.05). Use of SiRNA to block RASSF1A gene expression in murine cardiac fibroblast tissue culture led to increased fibroblast proliferation (p < 0.05). Methylation of the RASSF1A promoter region was significantly reduced in the TG hypoxic group compared to the WT hypoxic group (0.59 vs. 0.75, respectively). Based on our findings, we can speculate that EC-SOD significantly attenuates RASSF1A gene methylation and can alleviate cardiac fibrosis induced by hypoxia.

Project description:AIMS:Oxidative stress plays a crucial role in the pathogenesis of diabetic nephropathy (DN). We evaluated whether extracellular superoxide dismutase (EC-SOD) has a renoprotective effect through activation of adenosine monophosphate-activated protein kinase (AMPK) in diabetic kidneys. RESULTS:Human recombinant EC-SOD (hEC-SOD) was administered to 8-week-old male C57BLKS/J db/db mice through intraperitoneal injection once a week for 8 weeks. Renal SOD3 expression was suppressed in db/db mice, which was significantly enhanced by hEC-SOD treatment. hEC-SOD improved albuminuria, mesangial expansion, and interstitial fibrosis in db/db mice. At the molecular level, hEC-SOD increased phosphorylation of AMPK, activation of peroxisome proliferative-activated receptor ? coactivator 1? (PGC-1?), and dephosphorylation of forkhead box O transcription factor (FoxO)1 and FoxO3a. The protective effects of hEC-SOD were attributed to enhanced nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) and subsequently increased expression of NAD(P)H dehydrogenase 1 and heme oxygenase-1. Consequently, hEC-SOD recovered from systemic and renal inflammation and apoptosis, as reflected by the decreases of serum and renal monocyte chemoattractant protein-1 and tumor necrosis factor-? levels and increases of BCL-2/BAX ratio in diabetic kidney. hEC-SOD also improved oxidative stress and resulted in increased renal and urinary 8-hydroxy-2'-deoxyguanosine and 8-isoprostane levels in db/db mice. In cultured human glomerular endothelial cells, hEC-SOD ameliorated apoptosis and oxidative stress caused by high glucose exposure through activation of AMPK and PGC-1? and dephosphorylation of FoxOs. INNOVATION:These findings demonstrated for the first time that EC-SOD can potentially ameliorate hyperglycemia-induced oxidative stress, apoptosis, and inflammation through activation of AMPK and its downstream pathways in diabetic kidneys. CONCLUSIONS:EC-SOD is a potential therapeutic target for treatment of type 2 DN through intrarenal AMPK-PGC-1?-Nrf2 and AMPK-FoxOs signaling. Antioxid. Redox Signal. 28, 1543-1561.

Dataset Information

Extracellular superoxide dismutase (SOD3) regulates oxidative stress at the vitreoretinal interface.

Publications

Extracellular superoxide dismutase (SOD3) regulates oxidative stress at the vitreoretinal interface.

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