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TGR5 Receptor Activation Attenuates Diabetic Retinopathy Through Suppression of RhoA/ROCK Signaling

41 Pages Posted: 2 Oct 2019

See all articles by Lingpeng Zhu

Lingpeng Zhu

Nanjing Medical University - Center of Clinical Research

Wenjuan Wang

Nanjing Medical University - Center of Clinical Research

Tian-Hua Xie

Nanjing Medical University - Department of Ophthalmology

Jian Zou

Nanjing Medical University - Center of Clinical Research; Nanjing Medical University - Wuxi Institute of Translational Medicine

Xiaowei Nie

Nanjing Medical University - Center of Clinical Research

Xiaolu Wang

Nanjing Medical University - Center of Clinical Research

Meng-Yuan Zhang

Nanjing Medical University - Department of Ophthalmology

Zhong-Yuan Wang

Nanjing Medical University - Department of Ophthalmology

Shun Gu

Nanjing Medical University - Department of Ophthalmology

Miao Zhuang

Nanjing Medical University - Department of Ophthalmology

Jianxin Tan

Nanjing Medical University - Center of Clinical Research

Chenyou Shen

Nanjing Medical University - Center of Clinical Research

Youai Dai

Nanjing Medical University - Center of Clinical Research; Nanjing Medical University - Wuxi Institute of Translational Medicine

Xusheng Yang

Nanjing Medical University - Center of Clinical Research; Nanjing Medical University - Wuxi Institute of Translational Medicine

Yong Yao

Nanjing Medical University - Department of Ophthalmology

Ting-Ting Wei

Nanjing Medical University - Department of Ophthalmology

More...

Abstract

Background: Diabetic retinopathy is a common microvascular complication of diabetes mellitus. Abnormal energy metabolism in microvascular endothelium is involved in the progression of diabetic retinopathy. Bile Acid G-Protein-Coupled Membrane Receptor (TGR5) has emerged as a novel regulator of metabolic disorders. However, the role of TGR5 in diabetes mellitus-induced microvascular dysfunction in retinas is largely unknown.

Methods: ELISA was used for analyzing bile acid profiles in diabetic rat retinas and retinal microvascular endothelial cells (RMECs) cultured in high glucose medium. The effects of TGR5 agonist on streptozotocin-induced diabetic retinopathy were evaluated by HE staining, TUNEL staining, retinal trypsin digestion and vascular permeability assay. A pharmacological inhibitor of RhoA was used to study the role of TGR5 on the regulation of Rho/Rho-associated coiled-coil containing protein kinase (ROCK) and western blot, immunofluorescence and siRNA silencing were performed to study the related signaling pathways.

Findings: A decrease in bile acids was observed during DR progression in the diabetic rat retinas and RMECs cultured in high glucose medium. The TGR5 agonist obviously ameliorated diabetes-induced retinal microvascular dysfunction in vivo, and inhibited the effect of TNF-α on endothelial cell proliferation, migration, and permeability in vitro. On the contrary, knockdown of TGR5 by siRNA aggravated TNF-α-induced actin polymerization and endothelial permeability. Mechanistically, the effects of TGR5 on the improvement of endothelial function was due to its regulatory role on the ROCK signaling pathway. An inhibitor of RhoA significantly reversed the loss of tight junction protein under TNF-α stimulation.

Interpretation: Our findings suggest that insufficient bile acid signaling plays an important pathogenic role in the development of DR. Up-regulation or activation of TGR5 may inhibit RhoA/ROCK-dependent actin remodeling and represent an important therapeutic intervention for DR.

Funding Statement: This project was supported by the Natural Science Foundation of China (81770941, 81800845), Nanjing Medical University Science and Technology Development Fund (NMUB2018363) and Natural Science Foundation of Jiangsu Province (BK20190149, BK20180170).

Declaration of Interests: The authors declare that they have no competing interests.

Ethics Approval Statement: All animal experiments were performed according to the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health, and the procedures were approved by the Animal Care and Use Committee of Nanjing Medical University.

Keywords: Diabetic retinopathy; Bile acid; TGR5; RhoA/ROCK; vascular leakage

Suggested Citation

Zhu, Lingpeng and Wang, Wenjuan and Xie, Tian-Hua and Zou, Jian and Nie, Xiaowei and Wang, Xiaolu and Zhang, Meng-Yuan and Wang, Zhong-Yuan and Gu, Shun and Zhuang, Miao and Tan, Jianxin and Shen, Chenyou and Dai, Youai and Yang, Xusheng and Yao, Yong and Wei, Ting-Ting, TGR5 Receptor Activation Attenuates Diabetic Retinopathy Through Suppression of RhoA/ROCK Signaling (09/27/2019 02:01:15). Available at SSRN: https://ssrn.com/abstract=3460643 or http://dx.doi.org/10.2139/ssrn.3460643

Lingpeng Zhu

Nanjing Medical University - Center of Clinical Research

299 Qingyang Road
Jiangsu, Jiangsu 214023
China

Wenjuan Wang

Nanjing Medical University - Center of Clinical Research

299 Qingyang Road
Jiangsu, Jiangsu 214023
China

Tian-Hua Xie

Nanjing Medical University - Department of Ophthalmology

Jiangsu
China

Jian Zou

Nanjing Medical University - Center of Clinical Research ( email )

299 Qingyang Road
Wuxi, Jiangsu 214023
China

Nanjing Medical University - Wuxi Institute of Translational Medicine ( email )

Wuxi, Jiangsu 214023
China

Xiaowei Nie

Nanjing Medical University - Center of Clinical Research

299 Qingyang Road
Jiangsu, Jiangsu 214023
China

Xiaolu Wang

Nanjing Medical University - Center of Clinical Research ( email )

299 Qingyang Road
Jiangsu, Jiangsu 214023
China

Meng-Yuan Zhang

Nanjing Medical University - Department of Ophthalmology

Jiangsu
China

Zhong-Yuan Wang

Nanjing Medical University - Department of Ophthalmology

Jiangsu
China

Shun Gu

Nanjing Medical University - Department of Ophthalmology

Jiangsu
China

Miao Zhuang

Nanjing Medical University - Department of Ophthalmology

Jiangsu
China

Jianxin Tan

Nanjing Medical University - Center of Clinical Research

299 Qingyang Road
Jiangsu, Jiangsu 214023
China

Chenyou Shen

Nanjing Medical University - Center of Clinical Research

299 Qingyang Road
Jiangsu, Jiangsu 214023
China

Youai Dai

Nanjing Medical University - Center of Clinical Research

299 Qingyang Road
Jiangsu, Jiangsu 214023
China

Nanjing Medical University - Wuxi Institute of Translational Medicine

Wuxi, Jiangsu 214023
China

Xusheng Yang

Nanjing Medical University - Center of Clinical Research

299 Qingyang Road
Jiangsu, Jiangsu 214023
China

Nanjing Medical University - Wuxi Institute of Translational Medicine

Wuxi, Jiangsu 214023
China

Yong Yao (Contact Author)

Nanjing Medical University - Department of Ophthalmology ( email )

Jiangsu
China

Ting-Ting Wei

Nanjing Medical University - Department of Ophthalmology ( email )

Jiangsu
China

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