Endothelin-2 Injures the Blood–Retinal Barrier and Macroglial Müller Cells

Interactions with Angiotensin II, Aldosterone, and NADPH Oxidase

Saeed F. Alrashdi, Devy Deliyanti, Dean M. Talia, Jennifer L. Wilkinson-Berka

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Although increasing evidence indicates that endothelin-2 (Edn2) has distinct roles in tissue pathology, including inflammation, glial cell dysfunction, and angiogenesis, its role in the retina and the factors that regulate its actions are not fully understood. We hypothesized that Edn2 damages the blood–retinal barrier (BRB) and that this is mediated by interactions with the renin–angiotensin–aldosterone system and reactive oxygen species derived from NADPH oxidase (Nox). C57BL/6J mice received an intravitreal injection of Edn2 or control vehicle to examine the blood pressure–independent effects of Edn2. Mice administered Edn2 were randomized to receive by intraperitoneal injection treatments that inhibited the Edn type a receptor, Edn type b receptor, angiotensin type 1 receptor, mineralocorticoid receptor, or Nox isoforms 1 to 4. One month later, mice administered Edn2 exhibited breakdown of the BRB with increased vascular leakage, vascular endothelial growth factor expression, and infiltrating macrophages (Ly6C+CD45highCD11b+). Further, macroglial Müller cells, which influence the integrity of the BRB and prevent retinal edema, became gliotic and expressed increased levels of water (aquaporin-4) and ion (Kir4.1) channels. This Edn2-mediated retinopathy was reduced by all treatments. Complementary in vitro studies in cultured Müller cells supported these findings and demonstrated the importance of reactive oxygen species in mediating these events. In conclusion, Edn2 has detrimental effects on the BRB and Müller cells that involve interactions with the renin-angiotensin aldosterone system and Nox1/4.

Original languageEnglish
Pages (from-to)805-817
Number of pages13
JournalAmerican Journal of Pathology
Volume188
Issue number3
DOIs
Publication statusPublished - 1 Mar 2018

Cite this

@article{b70d472a67aa45c48fc109e0998ca72a,
title = "Endothelin-2 Injures the Blood–Retinal Barrier and Macroglial M{\"u}ller Cells: Interactions with Angiotensin II, Aldosterone, and NADPH Oxidase",
abstract = "Although increasing evidence indicates that endothelin-2 (Edn2) has distinct roles in tissue pathology, including inflammation, glial cell dysfunction, and angiogenesis, its role in the retina and the factors that regulate its actions are not fully understood. We hypothesized that Edn2 damages the blood–retinal barrier (BRB) and that this is mediated by interactions with the renin–angiotensin–aldosterone system and reactive oxygen species derived from NADPH oxidase (Nox). C57BL/6J mice received an intravitreal injection of Edn2 or control vehicle to examine the blood pressure–independent effects of Edn2. Mice administered Edn2 were randomized to receive by intraperitoneal injection treatments that inhibited the Edn type a receptor, Edn type b receptor, angiotensin type 1 receptor, mineralocorticoid receptor, or Nox isoforms 1 to 4. One month later, mice administered Edn2 exhibited breakdown of the BRB with increased vascular leakage, vascular endothelial growth factor expression, and infiltrating macrophages (Ly6C+CD45highCD11b+). Further, macroglial M{\"u}ller cells, which influence the integrity of the BRB and prevent retinal edema, became gliotic and expressed increased levels of water (aquaporin-4) and ion (Kir4.1) channels. This Edn2-mediated retinopathy was reduced by all treatments. Complementary in vitro studies in cultured M{\"u}ller cells supported these findings and demonstrated the importance of reactive oxygen species in mediating these events. In conclusion, Edn2 has detrimental effects on the BRB and M{\"u}ller cells that involve interactions with the renin-angiotensin aldosterone system and Nox1/4.",
author = "Alrashdi, {Saeed F.} and Devy Deliyanti and Talia, {Dean M.} and Wilkinson-Berka, {Jennifer L.}",
year = "2018",
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language = "English",
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journal = "American Journal of Pathology",
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Endothelin-2 Injures the Blood–Retinal Barrier and Macroglial Müller Cells : Interactions with Angiotensin II, Aldosterone, and NADPH Oxidase. / Alrashdi, Saeed F.; Deliyanti, Devy; Talia, Dean M.; Wilkinson-Berka, Jennifer L.

In: American Journal of Pathology, Vol. 188, No. 3, 01.03.2018, p. 805-817.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Endothelin-2 Injures the Blood–Retinal Barrier and Macroglial Müller Cells

T2 - Interactions with Angiotensin II, Aldosterone, and NADPH Oxidase

AU - Alrashdi, Saeed F.

AU - Deliyanti, Devy

AU - Talia, Dean M.

AU - Wilkinson-Berka, Jennifer L.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - Although increasing evidence indicates that endothelin-2 (Edn2) has distinct roles in tissue pathology, including inflammation, glial cell dysfunction, and angiogenesis, its role in the retina and the factors that regulate its actions are not fully understood. We hypothesized that Edn2 damages the blood–retinal barrier (BRB) and that this is mediated by interactions with the renin–angiotensin–aldosterone system and reactive oxygen species derived from NADPH oxidase (Nox). C57BL/6J mice received an intravitreal injection of Edn2 or control vehicle to examine the blood pressure–independent effects of Edn2. Mice administered Edn2 were randomized to receive by intraperitoneal injection treatments that inhibited the Edn type a receptor, Edn type b receptor, angiotensin type 1 receptor, mineralocorticoid receptor, or Nox isoforms 1 to 4. One month later, mice administered Edn2 exhibited breakdown of the BRB with increased vascular leakage, vascular endothelial growth factor expression, and infiltrating macrophages (Ly6C+CD45highCD11b+). Further, macroglial Müller cells, which influence the integrity of the BRB and prevent retinal edema, became gliotic and expressed increased levels of water (aquaporin-4) and ion (Kir4.1) channels. This Edn2-mediated retinopathy was reduced by all treatments. Complementary in vitro studies in cultured Müller cells supported these findings and demonstrated the importance of reactive oxygen species in mediating these events. In conclusion, Edn2 has detrimental effects on the BRB and Müller cells that involve interactions with the renin-angiotensin aldosterone system and Nox1/4.

AB - Although increasing evidence indicates that endothelin-2 (Edn2) has distinct roles in tissue pathology, including inflammation, glial cell dysfunction, and angiogenesis, its role in the retina and the factors that regulate its actions are not fully understood. We hypothesized that Edn2 damages the blood–retinal barrier (BRB) and that this is mediated by interactions with the renin–angiotensin–aldosterone system and reactive oxygen species derived from NADPH oxidase (Nox). C57BL/6J mice received an intravitreal injection of Edn2 or control vehicle to examine the blood pressure–independent effects of Edn2. Mice administered Edn2 were randomized to receive by intraperitoneal injection treatments that inhibited the Edn type a receptor, Edn type b receptor, angiotensin type 1 receptor, mineralocorticoid receptor, or Nox isoforms 1 to 4. One month later, mice administered Edn2 exhibited breakdown of the BRB with increased vascular leakage, vascular endothelial growth factor expression, and infiltrating macrophages (Ly6C+CD45highCD11b+). Further, macroglial Müller cells, which influence the integrity of the BRB and prevent retinal edema, became gliotic and expressed increased levels of water (aquaporin-4) and ion (Kir4.1) channels. This Edn2-mediated retinopathy was reduced by all treatments. Complementary in vitro studies in cultured Müller cells supported these findings and demonstrated the importance of reactive oxygen species in mediating these events. In conclusion, Edn2 has detrimental effects on the BRB and Müller cells that involve interactions with the renin-angiotensin aldosterone system and Nox1/4.

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U2 - 10.1016/j.ajpath.2017.11.009

DO - 10.1016/j.ajpath.2017.11.009

M3 - Article

VL - 188

SP - 805

EP - 817

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

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ER -