Eye and Brain (May 2022)
Involvement of High Mobility Group Box 1 Protein in Optic Nerve Damage in Diabetes
Abstract
Ghulam Mohammad,1 Renu A Kowluru1,2 1Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University, Detroit, MI, 48201, USA; 2Kresge Eye Institute, Wayne State University, Detroit, MI, 48201, USACorrespondence: Ghulam Mohammad, Tel +1 313-577-0744, Email [email protected]: Diabetic patients routinely have high levels of high mobility group box 1 (HMGB1) protein in their plasma, vitreous and ocular membranes, which is strongly correlated with subclinical chronic inflammation in the eye. Our previous work has suggested that high HMGB1 in diabetes plays a role in retinal inflammation and angiogenesis, but its role in the optic nerve damage is unclear. Therefore, our goal is to examine the role of HMGB1 in optic nerve damage in diabetes.Methods: Gene expression of HMGB1 was quantified in the optic nerve from streptozotocin-induced diabetic mice by qRT-PCR, and their protein expressions by Western blot analysis and immunofluorescence staining. Using immunohistochemical technique, expression of reactive astrogliosis (indicator of neuroinflammation) and nerve demyelination/damage were determined by quantifying glial fibrillary acid protein (GFAP) and myelin basic protein (MBP), respectively. The role of HMGB1 in the optic nerve damage and alteration visual pathways was confirmed in mice receiving glycyrrhizin, a HMGB1 inhibitor. Similar parameters were measured in the optic nerve from human donors with diabetes.Results: Compared to normal mice, diabetic mice exhibited increased levels of HMGB1, higher GFAP expression, and decreased MBP in the optic nerve. Double immunofluorescence microscopy revealed that diabetes induced increased HMGB1 immunoreactivities were significantly colocalized with GFAP in the optic nerve. Glycyrrhizin supplementation effectively reduced HMGB1 and maintained normal axonal myelination and visual conduction. Results from mice optic nerve confirmed the results obtained from human donors with diabetes.Discussions: Thus, diabetes-induced HMGB1 upregulation promotes optic nerve demyelination and inflammation. The regulation of HMGB1 activation has potential to protect optic nerve damage and the abnormalities of visual pathways in diabetic patients.Keywords: diabetes, visual function, optic nerve, inflammation, HMGB1
