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World J Diabetes. Jun 10, 2015; 6(5): 726-733
Published online Jun 10, 2015. doi: 10.4239/wjd.v6.i5.726
Functions of Müller cell-derived vascular endothelial growth factor in diabetic retinopathy
Juan-Juan Wang, Meili Zhu, Yun-Zheng Le
Juan-Juan Wang, Meili Zhu, Yun-Zheng Le, Department of Medicine Endocrinology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States
Juan-Juan Wang, Department of Ophthalmology, Huizhou Municipal Central Hospital, Huizhou 516000, Guangdong Province, China
Yun-Zheng Le, Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States
Yun-Zheng Le, Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States
Yun-Zheng Le, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States
Author contributions: All the authors equally contributed to this work.
Supported by The NIH grants, Nos. GM104934, EY020900 and EY021725 (NEI Core); Chinese National Natural Science Foundation grant, No. 81200699; grants from Presbyterian Health Foundation and Oklahoma Center for Adult Stem Cell Research, and an endowment from Choctaw Nation (to Le YZ).
Conflict-of-interest: None.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Yun-Zheng Le, PhD, Department of Medicine Endocrinology, University of Oklahoma Health Sciences Center, 941 S. L. Young Blvd., BSEB 302G, Oklahoma City, OK 73104, United States. yun-le@ouhsc.edu
Telephone: +1-405-2711087 Fax: +1-405-2713973
Received: September 18, 2014
Peer-review started: September 18, 2014
First decision: January 8, 2015
Revised: February 21, 2015
Accepted: March 16, 2015
Article in press: March 18, 2015
Published online: June 10, 2015
Abstract

Müller cells are macroglia and play many essential roles as supporting cells in the retina. To respond to pathological changes in diabetic retinopathy (DR), a major complication in the eye of diabetic patients, retinal Müller glia produce a high level of vascular endothelial growth factor (VEGF or VEGF-A). As VEGF is expressed by multiple retinal cell-types and Müller glia comprise only a small portion of cells in the retina, it has been a great challenge to reveal the function of VEGF or other globally expressed proteins produced by Müller cells. With the development of conditional gene targeting tools, it is now possible to dissect the function of Müller cell-derived VEGF in vivo. By using conditional gene targeting approach, we demonstrate that Müller glia are a major source of retinal VEGF in diabetic mice and Müller cell-derived VEGF plays a significant role in the alteration of protein expression and peroxynitration, which leads to retinal inflammation, neovascularization, vascular leakage, and vascular lesion, key pathological changes in DR. Therefore, Müller glia are a potential cellular target for the treatment of DR, a leading cause of blindness.

Keywords: Müller glia, Vascular endothelial growth factor, Protein modification, Inflammation, Blood-retina barriers, Diabetic retinopathy

Core tip: Diabetic retinopathy is a disorder of blood-retina barriers (BRBs) and neurons. Anti-vascular endothelial growth factor (VEGF) drugs are explored for treating BRB breakdown in the disease. As VEGF is also potentially beneficial, it is essential to understand the cellular and molecular mechanisms of VEGF action in the retina. Discussion is centered on the usefulness of conditional gene targeting mice in dissecting the function of globally expressed VEGF and in identifying significant roles for Müller glia-derived VEGF in diabetes-induced changes in protein expression/modification, inflammation, and BRB lesions and leakage.