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Asymmetric dimethylarginine aggravates blood–retinal barrier breakdown of diabetic retinopathy via inhibition of intercellular communication in retinal pericytes

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Abstract

Blood–retinal barrier breakdown is the main pathological characteristics of diabetic retinopathy (DR). Asymmetric dimethylarginine (ADMA) was reported to be elevated in DR patients. In this study, we observed the dynamic profile of ADMA, retinal morphology and permeability of BRB at 2, 4 or 8 week of diabetic rats induced by a single intraperitoneal injection of streptozocin (60 mg/kg) and in cultured rat retinal pericytes pretreated with d-glucose (30 mM) for 1, 3, 5 and 7 days or ADMA (3, 10, 30 μM) for 24, 48 and 72 h, trying to explore the effects of ADMA on blood–retinal barrier in DR. Gap junction intercellular communication (GJIC) and the expression of blood–retinal barrier-specific component connexin 43 (Cx43) were examined in diabetic rats or cultured retinal pericytes to elucidate whether ADMA impacted blood–retinal barrier function via damaging Cx43-GJIC. The results showed that with increasing duration of diabetes, the ultrastructure of blood–retinal barrier of diabetic rats appeared cell junction damage, apoptosis of retinal pericytes and breakdown of barrier successively. The increases in retinal permeability, ADMA levels and Cx43 expression, and abnormal GJIC were observed in diabetic rats and retinal pericytes exposed to d-glucose (30 mM). A glucose-like effect was seen using ADMA or another l-arginine analogue NG-monomethyl-l-arginine or dimethylarginine dimethylaminohydrolases (DDAHs) siRNA, implicating that ADMA aggravated the breakdown of blood–retinal barrier via damaging Cx43-GJIC.

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Abbreviations

DR:

Diabetic retinopathy

ADMA:

Asymmetric dimethylarginine

DDAH:

Dimethylarginine dimethylaminohydrolase

L-NMMA:

NG-Monomethyl-l-arginine

GJIC:

Gap junction intercellular communication

RPCs:

Retinal pericytes

BRB:

Blood–retinal barrier

Cx43:

Connexin 43

DM:

Diabetes mellitus

STZ:

Streptozotocin

EB:

Evans blue

TER:

Transcellular electrical resistance

HPLC:

High-performance liquid chromatography

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Acknowledgements

This work was supported by the grant from National Nature Science of China (nos. 81373408 and 81673432) and innovative project of Central South University (no. 2018zzts862).

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Authors and Affiliations

  1. Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, No. 110 Xiangya Road, Changsha, 410078, Hunan, People’s Republic of China

    Chu-Yi Huang, Ting Zhou, Ge Li, Xiao-Ming Xiong, Mei-Ting Wu & Jun-Lin Jiang

  2. Faculty of Medical Public Courses, Xinhua College of Sun Yat-sen University, Guangzhou, 510520, Guangdong, People’s Republic of China

    Ge Li

  3. Hunan Provincial Key Laboratory of Cardiovascular Research, Central South University, Changsha, 410078, Hunan, People’s Republic of China

    Xiao-Ming Xiong & Jun-Lin Jiang

  4. Department of Ophthalmology, Xiangya Third Hospital, Central South University, Changsha, 410008, People’s Republic of China

    Ming-Yuan Li

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  1. Chu-Yi Huang
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Contributions

J-LJ conceived the study, arranged the collaboration, and critically reviewed the manuscript. C-YH and TZ performed laboratory work and data analysis. C-YH and GL initiated the manuscript, edited and compiled the final version for submission. M-YL, X-MX and M-TW participated in its design and coordination. All authors read and approved the final manuscript.

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Correspondence to Jun-Lin Jiang.

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This article does not contain any studies with human participants performed by any of the authors. The experiments involving animals were conducted in accordance with the Guidelines on the Care and Use of Laboratory Animals issued by the Chinese Council on Animal Research (GB 14925-2001).

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Huang, CY., Zhou, T., Li, G. et al. Asymmetric dimethylarginine aggravates blood–retinal barrier breakdown of diabetic retinopathy via inhibition of intercellular communication in retinal pericytes. Amino Acids 51, 1515–1526 (2019). https://doi.org/10.1007/s00726-019-02788-1

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