Modulating expression of thioredoxin interacting protein (TXNIP) prevents secondary damage and preserves visual function in a mouse model of ischemia/reperfusion

Maha Coucha, Ahmed Y. Shanab, Mohamed Sayed, Almira Vazdarjanova, Azza B. El-Remessy

Research output: Contribution to journalArticle

Abstract

Retinal neurodegeneration, an early characteristic of several blinding diseases, triggers glial activation, resulting in inflammation, secondary damage and visual impairment. Treatments that aim only at neuroprotection have failed clinically. Here, we examine the impact of modulating thioredoxin interacting protein (TXNIP) to the inflammatory secondary damage and visual impairment in a model of ischemia/reperfusion (IR). Wild type (WT) and TXNIP knockout (TKO) mice underwent IR injury by increasing intraocular pressure for 40 min, followed by reperfusion. An additional group of WT mice received intravitreal TXNIP-antisense oligomers (ASO, 100 µg/2 µL) 2 days post IR injury. Activation of Müller glial cells, apoptosis and expression of inflammasome markers and visual function were assessed. IR injury triggered early TXNIP mRNA expression that persisted for 14 days and was localized within activated Müller cells in WT-IR, compared to sham controls. Exposure of Müller cells to hypoxia-reoxygenation injury triggered endoplasmic reticulum (ER) stress markers and inflammasome activation in WT cells, but not from TKO cells. Secondary damage was evident by the significant increase in the number of occluded acellular capillaries and visual impairment in IR-WT mice but not in IR-TKO. Intervention with TXNIP-ASO prevented ischemia-induced glial activation and neuro-vascular degeneration, and improved visual function compared to untreated WT. Targeting TXNIP expression may offer an effective approach in the prevention of secondary damage associated with retinal neurodegenerative diseases.

Original languageEnglish (US)
Article number3969
JournalInternational journal of molecular sciences
Volume20
Issue number16
DOIs
StatePublished - Aug 2 2019

Fingerprint

ischemia
Thioredoxins
Reperfusion
mice
Ischemia
damage
proteins
Proteins
Vision Disorders
Reperfusion Injury
Chemical activation
Neuroglia
Inflammasomes
impairment
activation
cells
markers
Neurodegenerative diseases
Cell Hypoxia
Retinal Diseases

Keywords

  • Inflammasome
  • Ischemia reperfusion
  • Retinal inflammation
  • TXNIP
  • Visual function

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

Modulating expression of thioredoxin interacting protein (TXNIP) prevents secondary damage and preserves visual function in a mouse model of ischemia/reperfusion. / Coucha, Maha; Shanab, Ahmed Y.; Sayed, Mohamed; Vazdarjanova, Almira; El-Remessy, Azza B.

In: International journal of molecular sciences, Vol. 20, No. 16, 3969, 02.08.2019.

Research output: Contribution to journalArticle

@article{582e4d75d8da4a22b667c08270896665,
title = "Modulating expression of thioredoxin interacting protein (TXNIP) prevents secondary damage and preserves visual function in a mouse model of ischemia/reperfusion",
abstract = "Retinal neurodegeneration, an early characteristic of several blinding diseases, triggers glial activation, resulting in inflammation, secondary damage and visual impairment. Treatments that aim only at neuroprotection have failed clinically. Here, we examine the impact of modulating thioredoxin interacting protein (TXNIP) to the inflammatory secondary damage and visual impairment in a model of ischemia/reperfusion (IR). Wild type (WT) and TXNIP knockout (TKO) mice underwent IR injury by increasing intraocular pressure for 40 min, followed by reperfusion. An additional group of WT mice received intravitreal TXNIP-antisense oligomers (ASO, 100 µg/2 µL) 2 days post IR injury. Activation of M{\"u}ller glial cells, apoptosis and expression of inflammasome markers and visual function were assessed. IR injury triggered early TXNIP mRNA expression that persisted for 14 days and was localized within activated M{\"u}ller cells in WT-IR, compared to sham controls. Exposure of M{\"u}ller cells to hypoxia-reoxygenation injury triggered endoplasmic reticulum (ER) stress markers and inflammasome activation in WT cells, but not from TKO cells. Secondary damage was evident by the significant increase in the number of occluded acellular capillaries and visual impairment in IR-WT mice but not in IR-TKO. Intervention with TXNIP-ASO prevented ischemia-induced glial activation and neuro-vascular degeneration, and improved visual function compared to untreated WT. Targeting TXNIP expression may offer an effective approach in the prevention of secondary damage associated with retinal neurodegenerative diseases.",
keywords = "Inflammasome, Ischemia reperfusion, Retinal inflammation, TXNIP, Visual function",
author = "Maha Coucha and Shanab, {Ahmed Y.} and Mohamed Sayed and Almira Vazdarjanova and El-Remessy, {Azza B.}",
year = "2019",
month = "8",
day = "2",
doi = "10.3390/ijms20163969",
language = "English (US)",
volume = "20",
journal = "International Journal of Molecular Sciences",
issn = "1661-6596",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "16",

}

TY - JOUR

T1 - Modulating expression of thioredoxin interacting protein (TXNIP) prevents secondary damage and preserves visual function in a mouse model of ischemia/reperfusion

AU - Coucha, Maha

AU - Shanab, Ahmed Y.

AU - Sayed, Mohamed

AU - Vazdarjanova, Almira

AU - El-Remessy, Azza B.

PY - 2019/8/2

Y1 - 2019/8/2

N2 - Retinal neurodegeneration, an early characteristic of several blinding diseases, triggers glial activation, resulting in inflammation, secondary damage and visual impairment. Treatments that aim only at neuroprotection have failed clinically. Here, we examine the impact of modulating thioredoxin interacting protein (TXNIP) to the inflammatory secondary damage and visual impairment in a model of ischemia/reperfusion (IR). Wild type (WT) and TXNIP knockout (TKO) mice underwent IR injury by increasing intraocular pressure for 40 min, followed by reperfusion. An additional group of WT mice received intravitreal TXNIP-antisense oligomers (ASO, 100 µg/2 µL) 2 days post IR injury. Activation of Müller glial cells, apoptosis and expression of inflammasome markers and visual function were assessed. IR injury triggered early TXNIP mRNA expression that persisted for 14 days and was localized within activated Müller cells in WT-IR, compared to sham controls. Exposure of Müller cells to hypoxia-reoxygenation injury triggered endoplasmic reticulum (ER) stress markers and inflammasome activation in WT cells, but not from TKO cells. Secondary damage was evident by the significant increase in the number of occluded acellular capillaries and visual impairment in IR-WT mice but not in IR-TKO. Intervention with TXNIP-ASO prevented ischemia-induced glial activation and neuro-vascular degeneration, and improved visual function compared to untreated WT. Targeting TXNIP expression may offer an effective approach in the prevention of secondary damage associated with retinal neurodegenerative diseases.

AB - Retinal neurodegeneration, an early characteristic of several blinding diseases, triggers glial activation, resulting in inflammation, secondary damage and visual impairment. Treatments that aim only at neuroprotection have failed clinically. Here, we examine the impact of modulating thioredoxin interacting protein (TXNIP) to the inflammatory secondary damage and visual impairment in a model of ischemia/reperfusion (IR). Wild type (WT) and TXNIP knockout (TKO) mice underwent IR injury by increasing intraocular pressure for 40 min, followed by reperfusion. An additional group of WT mice received intravitreal TXNIP-antisense oligomers (ASO, 100 µg/2 µL) 2 days post IR injury. Activation of Müller glial cells, apoptosis and expression of inflammasome markers and visual function were assessed. IR injury triggered early TXNIP mRNA expression that persisted for 14 days and was localized within activated Müller cells in WT-IR, compared to sham controls. Exposure of Müller cells to hypoxia-reoxygenation injury triggered endoplasmic reticulum (ER) stress markers and inflammasome activation in WT cells, but not from TKO cells. Secondary damage was evident by the significant increase in the number of occluded acellular capillaries and visual impairment in IR-WT mice but not in IR-TKO. Intervention with TXNIP-ASO prevented ischemia-induced glial activation and neuro-vascular degeneration, and improved visual function compared to untreated WT. Targeting TXNIP expression may offer an effective approach in the prevention of secondary damage associated with retinal neurodegenerative diseases.

KW - Inflammasome

KW - Ischemia reperfusion

KW - Retinal inflammation

KW - TXNIP

KW - Visual function

UR - http://www.scopus.com/inward/record.url?scp=85071496071&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85071496071&partnerID=8YFLogxK

U2 - 10.3390/ijms20163969

DO - 10.3390/ijms20163969

M3 - Article

C2 - 31443163

AN - SCOPUS:85071496071

VL - 20

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 16

M1 - 3969

ER -