Mesenchymal marker expression is elevated in Müller cells exposed to high glucose and in animal models of diabetic retinopathy

Abstract

// Ti Zhou 1, 2, * , Di Che 1, 2, * , Yuqing Lan 3, * , Zhenzhen Fang 2 , Jinye Xie 2 , HaiJun Gong 3 , ChaoYang Li 4 , Juan Feng 2 , Honghai Hong 2 , Weiwei Qi 2 , Caiqi Ma 2 , Zhonghan Yang 1 , WeiBin Cai 5 , Jun Zhong 1 , Jianxing Ma 6 , Xia Yang 1, 7 , Guoquan Gao 1, 2, 8 1 Program of Molecular Medicine, Affiliated Guangzhou Women and Children’s Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China 2 Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China 3 Department of Ophthalmology, Second Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China 4 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China 5 Guangdong Engineering and Technology Research Center for Disease-Model Animals, Sun Yat-Sen University, Guangzhou, China 6 Department of Physiology, University of Oklahoma, Health Sciences Center, Oklahoma City, Oklahoma, USA 7 Key Laboratory of Functional Molecules from Marine Microorganisms (Sun Yat-sen University), Department of Education of Guangdong Province, Guangzhou, China 8 China Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China * These authors contributed equally to this work Correspondence to: Guoquan Gao, email: gaogq@mail.sysu.edu.cn Xia Yang, email: yangxia@mail.sysu.edu.cn Jianxing Ma, email: jian-xing-ma@ouhsc.edu Keywords: diabetic retinopathy, mesenchymal markers, hyperglycemia, müller cells Received: June 06, 2016      Accepted: December 01, 2016      Published: December 15, 2016 ABSTRACT Müller cells are retinal glial cells and exhibit a fibroblast-like phenotype and ability to migrate in diabetic retinopathy (DR). However, expression of mesenchymal markers, which promote fibrosis in various organs, has not been characterized in the diabetic retina. We examined changes in the expression of these markers in Müller cells exposed to high glucose and in animal models of diabetic retinopathy. High glucose conditions increased mesenchymal maker expression and migration in Müller cells. Snail, N-cadherin, Vimentin, β-catenin, and α-smooth muscle actin (α-SMA) levels were all dramatically increased in retinas from humans with diabetic retinopathy (DR) and from DR mouse models. In addition, Snail overexpression increased the expression of connective tissue growth factor (CTGF) and fibronectin, while Snail knockdown attenuated high glucose-induced increases in fibronectin and CTGF expression. These results demonstrate for the first time that mesenchymal markers are upregulated in retinas from a diabetic mouse model, and that Snail and N-cadherin levels are also increased in Müller cells exposed to high glucose. This suggests mesenchymal proteins may play a crucial role in the development of DR.