title: Modulation of p75(NTR) prevents diabetes- and proNGF-induced retinal inflammation and blood-retina barrier breakdown in mice and rats.
abstract: OBJECTIVE
  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 (p75(NTR)), suggesting a possible pathological role of the proNGF-p75(NTR) 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 p75(NTR) would prevent diabetes- and proNGF-induced retinal inflammation and BRB breakdown.
  
  
  METHODS
  Diabetes was induced by streptozotocin in wild-type and p75(NTR) 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 p75(NTR) 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 p75(NTR) blunted the diabetes-induced decrease in retinal NGF expression and increases in proNGF, nuclear factor κB (NFκB), p-NFκB and TNF-α. Deletion of p75(NTR) also abrogated diabetes-induced glial fibrillary acidic protein expression, ganglion cell loss and vascular permeability. Inhibited expression or cleavage of p75(NTR) 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
  The proNGF-p75(NTR) axis contributes to retinal inflammation and vascular dysfunction in the rodent diabetic retina. These findings underscore the importance of p75(NTR) as a novel regulator of inflammation and potential therapeutic target in diabetic retinopathy.
authors.affiliation: Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, 1120 15th Street HM-1200, Augusta, GA 30912, USA.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Mysona
authors.forename: Mohammed M H
authors.initials: MM
authors.lastname: Al-Gayyar
authors.forename: Suraporn
authors.initials: S
authors.lastname: Matragoon
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Abdelsaid
authors.forename: Mona F
authors.initials: MF
authors.lastname: El-Azab
authors.forename: H Uri
authors.initials: HU
authors.lastname: Saragovi
authors.forename: Azza B
authors.initials: AB
authors.lastname: El-Remessy
mesh_terms: D000818:Animals; D001813:Blood-Retinal Barrier / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000378:metabolism*; D003930:Diabetic Retinopathy / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020800:Receptor, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D020800:Receptor, Nerve Growth Factor
references.citation: Prog Retin Eye Res. 2011 Sep;30(5):343-58
references.pmid: 21635964
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3817-22
references.pmid: 20133718
references.citation: Nat Rev Mol Cell Biol. 2002 Sep;3(9):673-84
references.pmid: 12209127
references.citation: Mol Vis. 2012;18:1411-20
references.pmid: 22690119
references.citation: Invest Ophthalmol Vis Sci. 2004 Sep;45(9):3330-6
references.pmid: 15326158
references.citation: J Neurosci. 2011 Feb 9;31(6):2292-304
references.pmid: 21307265
references.citation: Neuron. 2006 Apr 20;50(2):219-32
references.pmid: 16630834
references.citation: Proc Natl Acad Sci U S A. 2006 Nov 21;103(47):17939-43
references.pmid: 17093052
references.citation: Trends Neurosci. 2002 Jun;25(6):284-6
references.pmid: 12086739
references.citation: Shock. 2002 Jul;18(1):82-5
references.pmid: 12095140
references.citation: J Neurosci. 2005 Feb 9;25(6):1407-11
references.pmid: 15703394
references.citation: Invest Ophthalmol Vis Sci. 2011 Mar 10;52(3):1336-44
references.pmid: 21212173
references.citation: Exp Diabetes Res. 2007;2007:95103
references.pmid: 18274606
references.citation: Brain Res. 2008 Jun 27;1217:10-24
references.pmid: 18511024
references.citation: Pharmacotherapy. 2009 Feb;29(2):182-92
references.pmid: 19170588
references.citation: Nature. 2004 Feb 26;427(6977):843-8
references.pmid: 14985763
references.citation: J Biol Chem. 2005 Apr 15;280(15):14563-71
references.pmid: 15701642
references.citation: Mol Vis. 2012;18:2993-3003
references.pmid: 23288991
references.citation: J Comp Neurol. 2012 Mar 1;520(4):742-55
references.pmid: 21935940
references.citation: J Biol Chem. 1999 Jan 29;274(5):2597-600
references.pmid: 9915784
references.citation: Cell Tissue Res. 2009 Mar;335(3):477-88
references.pmid: 19156441
references.citation: Prog Neurobiol. 2002 Jun;67(3):203-33
references.pmid: 12169297
references.citation: J Biol Chem. 1999 Jul 23;274(30):21443-9
references.pmid: 10409708
references.citation: Diabetes. 2006 Sep;55(9):2401-11
references.pmid: 16936187
references.citation: Invest Ophthalmol Vis Sci. 2009 Aug;50(8):3860-8
references.pmid: 19264888
references.citation: Neurotox Res. 2009 Oct;16(3):255-60
references.pmid: 19526280
references.citation: J Neurosci. 2003 Jul 2;23(13):5425-36
references.pmid: 12843241
references.citation: Oncogene. 1998 Dec 24;17(25):3261-70
references.pmid: 9916988
references.citation: Invest Ophthalmol Vis Sci. 1998 Jan;39(1):212-6
references.pmid: 9430566
references.citation: Invest Ophthalmol Vis Sci. 2008 Jul;49(7):3239-44
references.pmid: 18378574
references.citation: Diabetologia. 2011 Mar;54(3):657-68
references.pmid: 20957344
references.citation: Trans Am Ophthalmol Soc. 2006;104:98-107
references.pmid: 17471330
references.citation: Science. 2001 Nov 30;294(5548):1945-8
references.pmid: 11729324
references.citation: Surv Ophthalmol. 2002 Dec;47 Suppl 2:S253-62
references.pmid: 12507627
references.citation: Cell. 1992 May 29;69(5):737-49
references.pmid: 1317267
references.citation: J Clin Invest. 1998 Aug 15;102(4):783-91
references.pmid: 9710447
references.citation: Diabetes. 2008 Apr;57(4):889-98
references.pmid: 18285558
references.citation: Am J Pathol. 2006 Jan;168(1):235-44
references.pmid: 16400026
references.citation: Brain Behav Evol. 2006;67(1):39-52
references.pmid: 16219997
references.citation: Diabetes. 2007 Sep;56(9):2380-7
references.pmid: 17536065
references.citation: Trends Neurosci. 2008 Feb;31(2):99-104
references.pmid: 18199491
references.citation: J Biol Chem. 2003 Oct 24;278(43):42161-9
references.pmid: 12913006
references.citation: Philos Trans R Soc Lond B Biol Sci. 2006 Sep 29;361(1473):1545-64
references.pmid: 16939974
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6226-30
references.pmid: 15026568
references.citation: Science. 1996 Apr 26;272(5261):542-5
references.pmid: 8614802
references.citation: J Clin Invest. 2002 Mar;109(6):805-15
references.pmid: 11901189
references.citation: Clin Exp Optom. 2005 May;88(3):132-45
references.pmid: 15926876
references.citation: Diabetologia. 2011 Mar;54(3):669-80
references.pmid: 21136036
references.citation: J Biol Chem. 1995 Mar 24;270(12):6564-9
references.pmid: 7896793