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

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

Research output: Contribution to journalArticle

31 Citations (Scopus)

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 p75 NTR-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.

Original languageEnglish (US)
Pages (from-to)2329-2339
Number of pages11
JournalDiabetologia
Volume56
Issue number10
DOIs
StatePublished - Oct 2013

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Nerve Growth Factor Receptor
Retina
Inflammation
Nerve Growth Factor
Retinal Vessels
Capillary Permeability
Diabetic Retinopathy
Ganglia
Rodentia
Glial Fibrillary Acidic Protein
Streptozocin
Knockout Mice
Neuroglia
Small Interfering RNA
Blood Cells

Keywords

  • BRB breakdown
  • Diabetic retinopathy
  • Ganglion loss
  • IL-1β
  • Inflammation
  • Müller cells
  • NFκB
  • TNF-α
  • p75KO
  • proNGF

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Mysona, B. A., Al-Gayyar, M. M. H., Matragoon, S., Abdelsaid, M. A., El-Azab, M. F., Saragovi, H. U., & El-Remessy, A. B. (2013). Modulation of p75NTR prevents diabetes- and proNGF-induced retinal inflammation and blood-retina barrier breakdown in mice and rats. Diabetologia, 56(10), 2329-2339. https://doi.org/10.1007/s00125-013-2998-6

Modulation of p75NTR prevents diabetes- and proNGF-induced retinal inflammation and blood-retina barrier breakdown in mice and rats. / Mysona, Barbara A.; Al-Gayyar, Mohammed M.H.; Matragoon, Suraporn; Abdelsaid, Mohammed A.; El-Azab, Mona F.; Saragovi, H. Uri; El-Remessy, Azza B.

In: Diabetologia, Vol. 56, No. 10, 10.2013, p. 2329-2339.

Research output: Contribution to journalArticle

Mysona, BA, Al-Gayyar, MMH, Matragoon, S, Abdelsaid, MA, El-Azab, MF, Saragovi, HU & El-Remessy, AB 2013, 'Modulation of p75NTR prevents diabetes- and proNGF-induced retinal inflammation and blood-retina barrier breakdown in mice and rats', Diabetologia, vol. 56, no. 10, pp. 2329-2339. https://doi.org/10.1007/s00125-013-2998-6
Mysona, Barbara A. ; Al-Gayyar, Mohammed M.H. ; Matragoon, Suraporn ; Abdelsaid, Mohammed A. ; El-Azab, Mona F. ; Saragovi, H. Uri ; El-Remessy, Azza B. / Modulation of p75NTR prevents diabetes- and proNGF-induced retinal inflammation and blood-retina barrier breakdown in mice and rats. In: Diabetologia. 2013 ; Vol. 56, No. 10. pp. 2329-2339.
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AU - Al-Gayyar, Mohammed M.H.

AU - Matragoon, Suraporn

AU - Abdelsaid, Mohammed A.

AU - El-Azab, Mona F.

AU - Saragovi, H. Uri

AU - El-Remessy, Azza B.

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N2 - 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 p75 NTR-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.

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