20(R)-ginsenoside Rg3 alleviates diabetic retinal injury in T2DM mice by attenuating ROS-mediated ER stress through the activation of the Nrf2/HO-1 axis

Wen-Lin Li; Ke Li; Wen-Guang Chang; Hui Shi; Wen-Xuan Zhang; Zi Wang; Wei Li

doi:10.1016/j.phymed.2024.156202

20(R)-ginsenoside Rg3 alleviates diabetic retinal injury in T2DM mice by attenuating ROS-mediated ER stress through the activation of the Nrf2/HO-1 axis

Phytomedicine. 2024 Nov 7:135:156202. doi: 10.1016/j.phymed.2024.156202. Online ahead of print.

Authors

Wen-Lin Li¹, Ke Li¹, Wen-Guang Chang², Hui Shi³, Wen-Xuan Zhang¹, Zi Wang⁴, Wei Li⁵

Affiliations

¹ College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China; College of Life Sciences, Engineering Research Center of the Chinese Ministry of Education for Bioreactor and Pharmaceutical Development, Jilin Agricultural University, Changchun, 130118, China; Jilin Provincial International Joint Research Center for the Development and Utilization of Authentic Medicinal Materials, Changchun, 130118, China.
² Institute for Translational Medicine, The Affiliated Hospital, Qingdao University, Qingdao, China.
³ The First Hospital, Jilin University, Changchun, 130118, China.
⁴ College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China; College of Life Sciences, Engineering Research Center of the Chinese Ministry of Education for Bioreactor and Pharmaceutical Development, Jilin Agricultural University, Changchun, 130118, China; Jilin Provincial International Joint Research Center for the Development and Utilization of Authentic Medicinal Materials, Changchun, 130118, China. Electronic address: wangzi8020@126.com.
⁵ College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China; College of Life Sciences, Engineering Research Center of the Chinese Ministry of Education for Bioreactor and Pharmaceutical Development, Jilin Agricultural University, Changchun, 130118, China; Jilin Provincial International Joint Research Center for the Development and Utilization of Authentic Medicinal Materials, Changchun, 130118, China. Electronic address: liwei7727@126.com.

PMID: 39579577
DOI: 10.1016/j.phymed.2024.156202

Abstract

Background: Although our previous work confirmed 20(R)-ginsenoside Rg3 (R-Rg3), which is an active ingredient in the Panax Ginseng C.A. Meyer, to have good anti-diabetic activity, its beneficial effect on diabetic retinal injury was found to be limited.

Purpose: This study aims to investigate the protective effects of R-Rg3 on diabetes-induced retinal injury and the associated molecular mechanisms of action.

Methods: Diabetic retinal injury was induced in mice using a combination of a high-fat diet (HFD) and intraperitoneal injection of streptozotocin (STZ). R-Rg3 (10 and 20 mg/kg) was subsequently administered for 6 weeks. The human retinal endothelial cells (HRECs) were subjected to high glucose (HG)-induced injury for the in vitro analysis and treated with R-Rg3 (4, 8, 16 μM), antioxidant N-Acetylcysteine (NAC, 1 mM) and Nrf2 inhibitor ML385 (5 μM). The mice retinas then underwent functional and histopathological analysis. Expression levels of proteins related to the Nrf2/HO-1 axis, tight junction proteins, endoplasmic reticulum (ER) stress and the apoptosis in retinal tissue and HRECs were determined by western blot. Expressions of ZO-1 and Nrf2 in the retina and HRECs were assessed by immunofluorescence. Additional evaluations included measuring body weights, fasting blood glucose (FBG), lipid levels and oxidative markers.

Results: The results showed 6 weeks of R-Rg3 treatment significantly restored the functional changes and redox system imbalance that was induced by HFD/STZ in mice. R-Rg3 was also found to significantly reduce retinal barrier damage and thickness changes resulting from hyperglycaemia exposure. At the same time, R-Rg3 also protected HRECs from HG-induced damage. R-Rg3 could also activate Nrf2/HO-1 axis and inhibit endoplasmic reticulum stress as a means of alleviating retinal endothelial cells apoptosis. The molecular docking results also demonstrated that R-Rg3 had a good binding ability with Nrf2.

Conclusion: Our study suggested Nrf2/HO-1 axis might be crucial for the ability of R-Rg3 to prevent diabetic retinal injury.

Keywords: 20(R)-ginsenoside Rg3; Apoptosis; Endoplasmic reticulum stress; Human retinal endothelial cells; Oxidative stress; Retinal injury.