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Amino Acids

, Volume 51, Issue 10–12, pp 1515–1526 | Cite as

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

  • Chu-Yi Huang
  • Ting Zhou
  • Ge Li
  • Ming-Yuan Li
  • Xiao-Ming Xiong
  • Mei-Ting Wu
  • Jun-Lin JiangEmail author
Original Article

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.

Keywords

Asymmetric dimethylarginine blood–retinal barrier dysfunction Diabetic retinopathy Connexin 43 Gap junction intercellular communication 

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

Notes

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).

Author 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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human participants and/or animals

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).

Informed consent

This article does not contain any studies with human participants performed by any of the authors.

Supplementary material

726_2019_2788_MOESM1_ESM.doc (3 mb)
Supplementary material 1 (DOC 3123 kb)

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Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmacology, Xiangya School of Pharmaceutical SciencesCentral South UniversityChangshaPeople’s Republic of China
  2. 2.Faculty of Medical Public CoursesXinhua College of Sun Yat-sen UniversityGuangzhouPeople’s Republic of China
  3. 3.Hunan Provincial Key Laboratory of Cardiovascular ResearchCentral South UniversityChangshaPeople’s Republic of China
  4. 4.Department of OphthalmologyXiangya Third Hospital, Central South UniversityChangshaPeople’s Republic of China

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