Inhibition of HMGB1 protects the retina from ischemia-reperfusion, as well as reduces insulin resistance proteins.

Li Liu, Youde Jiang, Jena J Steinle

PloS one 2017

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The role of inflammation in diabetic retinal amage is well accepted. While a number of cytokines and inflammatory mediators are responsible for these changes, upstream regulators are less well studied. Additionally, the role for these upstream mediators in retinal health is unclear. In this study, we hypothesized that inhibition of high mobility group box 1 (HMGB1) could restore normal insulin signaling in retinal endothelial cells (REC) grown in high glucose, as well as protect the retina against ischemia/reperfusion (I/R)-induced retinal damage. REC were grown in normal (5mM) or high glucose (25mM) and treated with Box A or glycyrrhizin, two different HMGB1 inhibitors. Western blotting was done for HMGB1, toll-like receptor 4 (TLR4), insulin receptor, insulin receptor substrate-1 (IRS-1), and Akt. ELISA analyses were done for tumor necrosis factor alpha (TNFα) and cleaved caspase 3. In addition, C57/B6 mice were treated with glycyrrhizin, both before and after ocular I/R. Two days following I/R, retinal sections were processed for neuronal changes, while vascular damage was measured at 10 days post-I/R. Results demonstrate that both Box A and glycyrrhizin reduced HMGB1, TLR4, and TNFα levels in REC grown in high glucose. This led to reduced cleavage of caspase 3 and IRS-1Ser307 phosphorylation, and increased insulin receptor and Akt phosphorylation. Glycyrrhizin treatment significantly reduced loss of retinal thickness and degenerate capillary numbers in mice exposed to I/R. Taken together, these results suggest that inhibition of HMGB1 can reduce retinal insulin resistance, as well as protect the retina against I/R-induced damage.

Citation

Li Liu, Youde Jiang, Jena J Steinle. Inhibition of HMGB1 protects the retina from ischemia-reperfusion, as well as reduces insulin resistance proteins. PloS one. 2017;12(5):e0178236