Sustained Inhibition of NF-KB Activity Mitigates Retinal Vasculopathy in Diabetes

摘要

This study investigated the effects of long-term NF-KB inhibition in mitigating retinal vasculopathy in a type 1 diabetic mouse model (Akita, Ins2Akita). Akita and wild-type (C57BL/6J) male mice, 24 to 26 weeks old, were treated with or without a selective inhibitor of NF-KB, 4-methyl-N1-(3-phenyl-propyl) benzene-1,2-diamine (JSH-23), for 4 weeks. Treatment was given when the mice were at least 24 weeks old. Metabolic parameters, key inflammatory mediators, blood-retinal barrier junction molecules, retinal structure, and function were measured. JSH-23 significantly lowered basal glucose levels and intraocular pressure in Akita. It also mitigated vascular remodeling and microaneurysms significantly. Optical coherence tomography of untreated Akita showed thinning of retinal layers; however, treatment with JSH-23 could prevent it. Electroretinogram demonstrated that A- and B-waves in Akita were significantly smaller than in wild type mice, indicating that JSH-23 intervention prevented loss of retinal function. Protein levels and gene expression of key inflammatory mediators, such as NOD-like receptor family pyrin domain-containing 3, intercellular adhesion molecule-1, inducible nitric oxide synthase, and cyclooxygenase-2, were decreased after JSH-23 treatment. At the same time, connexin43 and occludin were maintained. Vision-guided behavior also improved significantly. The results show that reducing inflammation could protect the diabetic retina and its vasculature. Findings appear to have broader implications in treating not only ocular conditions but also other vasculopathies. (Am J Pathol 2021, 191: 947e964; https://doi.org/10.1016/j.ajpath.2021.01.016)