Peroxynitrite mediates retinal neurodegeneration by inhibiting nerve growth factor survival signaling in experimental and human diabetes

Tayyeba K. Ali, Suraporn Matragoon, Bindu A. Pillai, Gregory I Liou, Azza B. El-Remessy

Research output: Contribution to journalArticle

104 Citations (Scopus)

Abstract

OBJECTIVE-Recently we have shown that diabetes-induced retinal neurodegeneration positively correlates with oxidative stress and peroxynitrite. Studies also show that peroxynitrite impairs nerve growth factor (NGF) survival signaling in sensory neurons. However, the causal role of peroxynitrite and the impact of tyrosine nitration on diabetes-induced retinal neurode-generation and NGF survival signaling have not been elucidated. RESEARCH DESIGN AND METHODS-Expression of NGF and its receptors was examined in retinas from human and streptozotocin-induced diabetic rats and retinal ganglion cells (RGCs). Diabetic animals were treated with FeTPPS (15 mg · kg -1 · day -1 ip), which catalytically decomposes peroxynitrite to nitrate. After 4 weeks of diabetes, retinal cell death was determined by TUNEL assay. Lipid peroxidation and nitrotyrosine were determined using MDA assay, immunofluorescence, and Slot-Blot analysis. Expression of NGF and its receptors was determined by enzyme-linked immunosorbent assay (ELISA), real-time PCR, immunoprecipitation, and Western blot analyses. RESULTS-Analyses of retinal neuronal death and NGF showed ninefold and twofold increases, respectively, in diabetic retinas compared with controls. Diabetes also induced increases in lipid peroxidation, nitrotyrosine, and the pro-apoptotic p75 NTR receptor in human and rat retinas. These effects were associated with tyrosine nitration of the pro-survival TrkA receptor, resulting in diminished phosphorylation of TrkA and its downstream target, Akt. Furthermore, peroxynitrite induced neuronal death, TrkA nitration, and activation of p38 mitogen-activated protein kinase (MAPK) in RGCs, even in the presence of exogenous NGF. FeTPPS prevented tyrosine nitration, restored NGF survival signal, and prevented neuronal death in vitro and in vivo. CONCLUSIONS-Together, these data suggest that diabetes-induced peroxynitrite impairs NGF neuronal survival by nitrating TrkA receptor and enhancing p75 NTR expression.

Original languageEnglish (US)
Pages (from-to)889-898
Number of pages10
JournalDiabetes
Volume57
Issue number4
DOIs
StatePublished - Apr 1 2008

Fingerprint

Peroxynitrous Acid
Nerve Growth Factor
trkA Receptor
Nerve Growth Factor Receptors
Tyrosine
Retina
Retinal Ganglion Cells
Lipid Peroxidation
In Situ Nick-End Labeling
p38 Mitogen-Activated Protein Kinases
Sensory Receptor Cells
Streptozocin
Immunoprecipitation
Nitrates
Fluorescent Antibody Technique
Real-Time Polymerase Chain Reaction
Oxidative Stress
Cell Death
Research Design
Western Blotting

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Peroxynitrite mediates retinal neurodegeneration by inhibiting nerve growth factor survival signaling in experimental and human diabetes. / Ali, Tayyeba K.; Matragoon, Suraporn; Pillai, Bindu A.; Liou, Gregory I; El-Remessy, Azza B.

In: Diabetes, Vol. 57, No. 4, 01.04.2008, p. 889-898.

Research output: Contribution to journalArticle

Ali, Tayyeba K. ; Matragoon, Suraporn ; Pillai, Bindu A. ; Liou, Gregory I ; El-Remessy, Azza B. / Peroxynitrite mediates retinal neurodegeneration by inhibiting nerve growth factor survival signaling in experimental and human diabetes. In: Diabetes. 2008 ; Vol. 57, No. 4. pp. 889-898.
@article{16f977d33a124882a9e19c57f486eaf0,
title = "Peroxynitrite mediates retinal neurodegeneration by inhibiting nerve growth factor survival signaling in experimental and human diabetes",
abstract = "OBJECTIVE-Recently we have shown that diabetes-induced retinal neurodegeneration positively correlates with oxidative stress and peroxynitrite. Studies also show that peroxynitrite impairs nerve growth factor (NGF) survival signaling in sensory neurons. However, the causal role of peroxynitrite and the impact of tyrosine nitration on diabetes-induced retinal neurode-generation and NGF survival signaling have not been elucidated. RESEARCH DESIGN AND METHODS-Expression of NGF and its receptors was examined in retinas from human and streptozotocin-induced diabetic rats and retinal ganglion cells (RGCs). Diabetic animals were treated with FeTPPS (15 mg · kg -1 · day -1 ip), which catalytically decomposes peroxynitrite to nitrate. After 4 weeks of diabetes, retinal cell death was determined by TUNEL assay. Lipid peroxidation and nitrotyrosine were determined using MDA assay, immunofluorescence, and Slot-Blot analysis. Expression of NGF and its receptors was determined by enzyme-linked immunosorbent assay (ELISA), real-time PCR, immunoprecipitation, and Western blot analyses. RESULTS-Analyses of retinal neuronal death and NGF showed ninefold and twofold increases, respectively, in diabetic retinas compared with controls. Diabetes also induced increases in lipid peroxidation, nitrotyrosine, and the pro-apoptotic p75 NTR receptor in human and rat retinas. These effects were associated with tyrosine nitration of the pro-survival TrkA receptor, resulting in diminished phosphorylation of TrkA and its downstream target, Akt. Furthermore, peroxynitrite induced neuronal death, TrkA nitration, and activation of p38 mitogen-activated protein kinase (MAPK) in RGCs, even in the presence of exogenous NGF. FeTPPS prevented tyrosine nitration, restored NGF survival signal, and prevented neuronal death in vitro and in vivo. CONCLUSIONS-Together, these data suggest that diabetes-induced peroxynitrite impairs NGF neuronal survival by nitrating TrkA receptor and enhancing p75 NTR expression.",
author = "Ali, {Tayyeba K.} and Suraporn Matragoon and Pillai, {Bindu A.} and Liou, {Gregory I} and El-Remessy, {Azza B.}",
year = "2008",
month = "4",
day = "1",
doi = "10.2337/db07-1669",
language = "English (US)",
volume = "57",
pages = "889--898",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "4",

}

TY - JOUR

T1 - Peroxynitrite mediates retinal neurodegeneration by inhibiting nerve growth factor survival signaling in experimental and human diabetes

AU - Ali, Tayyeba K.

AU - Matragoon, Suraporn

AU - Pillai, Bindu A.

AU - Liou, Gregory I

AU - El-Remessy, Azza B.

PY - 2008/4/1

Y1 - 2008/4/1

N2 - OBJECTIVE-Recently we have shown that diabetes-induced retinal neurodegeneration positively correlates with oxidative stress and peroxynitrite. Studies also show that peroxynitrite impairs nerve growth factor (NGF) survival signaling in sensory neurons. However, the causal role of peroxynitrite and the impact of tyrosine nitration on diabetes-induced retinal neurode-generation and NGF survival signaling have not been elucidated. RESEARCH DESIGN AND METHODS-Expression of NGF and its receptors was examined in retinas from human and streptozotocin-induced diabetic rats and retinal ganglion cells (RGCs). Diabetic animals were treated with FeTPPS (15 mg · kg -1 · day -1 ip), which catalytically decomposes peroxynitrite to nitrate. After 4 weeks of diabetes, retinal cell death was determined by TUNEL assay. Lipid peroxidation and nitrotyrosine were determined using MDA assay, immunofluorescence, and Slot-Blot analysis. Expression of NGF and its receptors was determined by enzyme-linked immunosorbent assay (ELISA), real-time PCR, immunoprecipitation, and Western blot analyses. RESULTS-Analyses of retinal neuronal death and NGF showed ninefold and twofold increases, respectively, in diabetic retinas compared with controls. Diabetes also induced increases in lipid peroxidation, nitrotyrosine, and the pro-apoptotic p75 NTR receptor in human and rat retinas. These effects were associated with tyrosine nitration of the pro-survival TrkA receptor, resulting in diminished phosphorylation of TrkA and its downstream target, Akt. Furthermore, peroxynitrite induced neuronal death, TrkA nitration, and activation of p38 mitogen-activated protein kinase (MAPK) in RGCs, even in the presence of exogenous NGF. FeTPPS prevented tyrosine nitration, restored NGF survival signal, and prevented neuronal death in vitro and in vivo. CONCLUSIONS-Together, these data suggest that diabetes-induced peroxynitrite impairs NGF neuronal survival by nitrating TrkA receptor and enhancing p75 NTR expression.

AB - OBJECTIVE-Recently we have shown that diabetes-induced retinal neurodegeneration positively correlates with oxidative stress and peroxynitrite. Studies also show that peroxynitrite impairs nerve growth factor (NGF) survival signaling in sensory neurons. However, the causal role of peroxynitrite and the impact of tyrosine nitration on diabetes-induced retinal neurode-generation and NGF survival signaling have not been elucidated. RESEARCH DESIGN AND METHODS-Expression of NGF and its receptors was examined in retinas from human and streptozotocin-induced diabetic rats and retinal ganglion cells (RGCs). Diabetic animals were treated with FeTPPS (15 mg · kg -1 · day -1 ip), which catalytically decomposes peroxynitrite to nitrate. After 4 weeks of diabetes, retinal cell death was determined by TUNEL assay. Lipid peroxidation and nitrotyrosine were determined using MDA assay, immunofluorescence, and Slot-Blot analysis. Expression of NGF and its receptors was determined by enzyme-linked immunosorbent assay (ELISA), real-time PCR, immunoprecipitation, and Western blot analyses. RESULTS-Analyses of retinal neuronal death and NGF showed ninefold and twofold increases, respectively, in diabetic retinas compared with controls. Diabetes also induced increases in lipid peroxidation, nitrotyrosine, and the pro-apoptotic p75 NTR receptor in human and rat retinas. These effects were associated with tyrosine nitration of the pro-survival TrkA receptor, resulting in diminished phosphorylation of TrkA and its downstream target, Akt. Furthermore, peroxynitrite induced neuronal death, TrkA nitration, and activation of p38 mitogen-activated protein kinase (MAPK) in RGCs, even in the presence of exogenous NGF. FeTPPS prevented tyrosine nitration, restored NGF survival signal, and prevented neuronal death in vitro and in vivo. CONCLUSIONS-Together, these data suggest that diabetes-induced peroxynitrite impairs NGF neuronal survival by nitrating TrkA receptor and enhancing p75 NTR expression.

UR - http://www.scopus.com/inward/record.url?scp=42449100783&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=42449100783&partnerID=8YFLogxK

U2 - 10.2337/db07-1669

DO - 10.2337/db07-1669

M3 - Article

C2 - 18285558

AN - SCOPUS:42449100783

VL - 57

SP - 889

EP - 898

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 4

ER -