• Akira Imai, Yuichi Toriyama, Yasuhiro Iesato, Kazutaka Hirabayashi, Takayuki Sakurai, Akiko Kamiyoshi, Yuka Ichikawa-Shindo, Hisaka Kawate, Megumu Tanaka, Tian Liu, Xian Xian, Liuyu Zhai, Kun Dai, Keiya Tanimura, Teng Liu, Nanqi Cui, Akihiro Yamauchi, Toshinori Murata, and Takayuki Shindo.
• Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan; Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan.
• Am. J. Pathol. 2017 May 1; 187 (5): 999-1015.

AbstractDiabetic macular edema (DME) is caused by blood-retinal barrier breakdown associated with retinal vascular hyperpermeability and inflammation, and it is the major cause of visual dysfunction in diabetic retinopathy. Adrenomedullin (ADM) is an endogenous peptide first identified as a strong vasodilator. ADM is expressed in the eyes and is up-regulated in various eye diseases, although the pathophysiological significance is largely unknown. We investigated the effect of ADM on DME. In Kimba mice, which overexpress human vascular endothelial growth factor in their retinas, the capillary dropout, vascular leakage, and vascular fragility characteristic of diabetic retinopathy were observed. Intravitreal or systemic administration of ADM to Kimba mice ameliorated both the capillary dropout and vascular leakage. Evaluation of the transendothelial electrical resistance and fluorescein isothiocyanate-dextran permeability of an endothelial cell monolayer using TR-iBRB retinal capillary endothelial cells revealed that vascular endothelial growth factor enhanced vascular permeability but that co-administration of ADM suppressed the effect, in part by enhancing tight junction formation between endothelial cells. In addition, a comprehensive PCR array analysis showed that ADM administration suppressed various molecules related to inflammation and NF-κB signaling within retinas. From these results, we suggest that by exerting inhibitory effects on retinal inflammation, vascular permeability, and blood-retinal barrier breakdown, ADM could serve as a novel therapeutic agent for the treatment of DME.Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

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