Protective Effects of Nattokinase Against Microvascular Abnormalities and Neuroinflammation by Regulating HMGB1 Signaling in Diabetic Retinopathy

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Protective Effects of Nattokinase Against Microvascular Abnormalities and Neuroinflammation by Regulating HMGB1 Signaling in Diabetic Retinopathy 35 Pages Posted: 16 May 2022 See all articles by Zijing HuangZijing HuangShantou University - Joint Shantou International Eye CenterXiaowei SunQingdao University - Department of OphthalmologyWai Kit ChuPrince of Wales Hospital - The Chinese University of Hong KongTsz Kin NgShantou University - Joint Shantou International Eye CenterShaolang ChenShantou University - Joint Shantou International Eye CenterJiajian LiangShantou University - Joint Shantou International Eye CenterChongbo ChenShantou University - Joint Shantou International Eye CenterYanxuan XuShantou University - Joint Shantou International Eye CenterQingping LiuShantou University - Joint Shantou International Eye CenterWeiqi ChenShantou University - Joint Shantou International Eye CenterDingguo HuangShantou University - Joint Shantou International Eye Center More... Abstract Background: Diabetic retinopathy (DR) has become a significant major public health issue worldwide. Nattokinase (NK), an active ingredient in natto, exerts diverse beneficial cardiovascular effects. We investigated the therapeutic potential of NK in DR and explored the underlying molecular mechanism.Methods: A mouse diabetes model was established by intraperitoneal injection of streptozotocin. Microvascular leakage was examined using Evans blue assay. Pericytes loss was evaluated using nerve/glial antigen 2 (NG2) immunolabeling. Glial activation and leukostasis were detected with fluorescence assays. The role of high mobility group box 1 (HMGB1) and its downstream signaling molecules upon NK treatment was indicated by PCR array and validated with western blot and immunostaining. The protective roles of NK were verified in human retinal micrangium endothelial cells (HRMECs) treated with high glucose.Findings: NK significantly improved blood-retinal barrier integrity as shown in reduced vascular permeability, upregulated expression of endothelial tight junction proteins, and increased survival of pericytes in diabetic retinas, as well as the decreased HRMECs migration under high glucose insults. NK was able to orchestrate high glucose-induced glial activation and anti-inflammation cascade. Mechanically, the therapeutical effects of NK were at least in part mediated through the inhibiting the HMGB1 signaling in activated microglia. NK also exerted potent protective effects against diabetes-induced neuronal injury. Interpretation: Our data demonstrated protective effects of NK against microvascular damages and HMGB1-mediated neuroinflammation, suggesting that NK could be developed as a novel pharmaceutical agent for the treatment of DR.Funding Information: This work was supported by the National Natural Science Foundation of China (No. 291 82101112).Declaration of Interests: The authors declare that they have no financial conflicts.Ethics Approval Statement: This study was carried out in accordance with the Association for Research in Vision and Ophthalmology (ARVO) Statement for Use of Animals in Ophthalmic and Vision Research and were approved by the local Animal Ethic Committee of Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong. Keywords: Diabetic retinopathy, Nattokinase, vascular leakage, neuroinflammation, high mobility group box 1 (HMGB1). Suggested Citation: Suggested Citation Huang, Zijing and Sun, Xiaowei and Chu, Wai Kit and Ng, Tsz Kin and Chen, Shaolang and Liang, Jiajian and Chen, Chongbo and Xu, Yanxuan and Liu, Qingping and Chen, Weiqi and Huang, Dingguo, Protective Effects of Nattokinase Against Microvascular Abnormalities and Neuroinflammation by Regulating HMGB1 Signaling in Diabetic Retinopathy. Available at SSRN: https://ssrn.com/abstract=4111083 Zijing Huang (Contact Author) Shantou University - Joint Shantou International Eye Center ( email ) Xiaowei Sun Qingdao University - Department of Ophthalmology ( email ) China Wai Kit Chu Prince of Wales Hospital - The Chinese University of Hong Kong ( email ) China Tsz Kin Ng Shantou University - Joint Shantou International Eye Center ( email ) Shaolang Chen Shantou University - Joint Shantou International Eye Center ( email ) Jiajian Liang Shantou University - Joint Shantou International Eye Center ( email ) Chongbo Chen Shantou University - Joint Shantou International Eye Center ( email ) Yanxuan Xu Shantou University - Joint Shantou International Eye Center ( email ) Qingping Liu Shantou University - Joint Shantou International Eye Center ( email ) Weiqi Chen Shantou University - Joint Shantou International Eye Center ( email ) Dingguo Huang Shantou University - Joint Shantou International Eye Center ( email ) Download This Paper Open PDF in Browser Please enable JavaScript to view the comments powered by Disqus. 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