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Diabetologia
Published in: Diabetologia 10/2013

01-10-2013 | Article

Modulation of p75NTR prevents diabetes- and proNGF-induced retinal inflammation and blood–retina barrier breakdown in mice and rats

Authors: Barbara A. Mysona, Mohammed M. H. Al-Gayyar, Suraporn Matragoon, Mohammed A. Abdelsaid, Mona F. El-Azab, H. Uri Saragovi, Azza B. El-Remessy

Published in: Diabetologia | Issue 10/2013

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Abstract

Aims/hypothesis

Diabetic retinopathy is characterised by early blood–retina barrier (BRB) breakdown and neurodegeneration. Diabetes causes imbalance of nerve growth factor (NGF), leading to accumulation of the NGF precursor (proNGF), as well as the NGF receptor, p75 neurotrophin receptor (p75NTR), suggesting a possible pathological role of the proNGF–p75NTR axis in the diabetic retina. To date, the role of this axis in diabetes-induced retinal inflammation and BRB breakdown has not been explored. We hypothesised that modulating p75NTR would prevent diabetes- and proNGF-induced retinal inflammation and BRB breakdown.

Methods

Diabetes was induced by streptozotocin in wild-type and p75NTR knockout (p75KO) mice. After 5 weeks, the expression of inflammatory mediators, ganglion cell loss and BRB breakdown were determined. Cleavage-resistant proNGF was overexpressed in rodent retinas with and without p75NTR short hairpin RNA or with pharmacological inhibitors. In vitro, the effects of proNGF were investigated in retinal Müller glial cell line (rMC-1) and primary Müller cells.

Results

Deletion of p75NTR blunted the diabetes-induced decrease in retinal NGF expression and increases in proNGF, nuclear factor κB (NFκB), p-NFκB and TNF-α. Deletion of p75NTR also abrogated diabetes-induced glial fibrillary acidic protein expression, ganglion cell loss and vascular permeability. Inhibited expression or cleavage of p75NTR blunted proNGF-induced retinal inflammation and vascular permeability. In vitro, proNGF induced p75NTR-dependent production of inflammatory mediators in primary wild-type Müller and rMC-1 cultures, but not in p75KO Müller cells.

Conclusions/interpretation

The proNGF–p75NTR axis contributes to retinal inflammation and vascular dysfunction in the rodent diabetic retina. These findings underscore the importance of p75NTR as a novel regulator of inflammation and potential therapeutic target in diabetic retinopathy.
Appendix
Available only for authorised users
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Metadata
Title
Modulation of p75NTR prevents diabetes- and proNGF-induced retinal inflammation and blood–retina barrier breakdown in mice and rats
Authors
Barbara A. Mysona
Mohammed M. H. Al-Gayyar
Suraporn Matragoon
Mohammed A. Abdelsaid
Mona F. El-Azab
H. Uri Saragovi
Azza B. El-Remessy
Publication date
01-10-2013
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 10/2013
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-013-2998-6

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