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Xiang Ren, John D Ash, Li Kong; Thioredoxin plays a key role in retinal neuropathy prior to endothelial damage in diabetic mice. Invest. Ophthalmol. Vis. Sci. 2017;58(8):88.
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Hyperglycemia is one of the major characteristics of diabetes. Hyperglycemia increases the risk of diabetic retinopathy (DR), long-term morbidity, and mortality. Moreover, emerging evidence suggests that neuronal damage occurs before microvascular complications in DR patients, but the underlying mechanism is unclear. Thioredoxin (Trx) is a small molecular protein which plays a key role in anti-apoptosis, anti-oxidation, proliferation, and survival. We investigated the role of Trx in diabetes-induced retinal neuropathy in order to identify new therapeutic targets for the clinical treatment and prevention of DR.
For in vivo studies, a high-fat diet and STZ injection were used to generate a mouse model of DR. Histology was utilized to examine tissue morphology and measure the outer nuclear layer thickness. Electroretinography (ERG) were used to assess retinal function. For in vitro studies, Neuro2a and HUVEC cells were incubated in normal glucose (5.5 mM) and high-glucose (30 mM) medium. Both in vivo and in vitro, we used sulforaphane, an up-regulator of Trx, and PX12, an inhibitor of Trx, modulate Trx levels. Flow cytometry assays were performed to quantify levels of apoptosis. Real-time PCR, Western blotting, and immunohistochemistry were carried out to determine gene and protein expression in vitro and in vivo. All animal procedures were conducted in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.
Retinal neuropathy occurred before endothelial damage in cells with high glucose and in DR mice, which corresponded with decreases in expression of Trx. Apoptosis signal-regulating kinase-1 (ASK1), Trx-interacting protein (Txnip), and phosho-p38 were increased both on the mRNA and protein level in high glucose cells and DR mice.
These results suggest that retinal neuropathy occurs prior to endothelial damage induced by diabetes, and that Trx plays a key role in this process. This underlying mechanism may be related to activation of the Trx/ASK1/p-p38/Trxnip pathway.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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