Role of ocular complement factor H in a murine model of choroidal neovascularization.
The objective of this study was to explore the relationship between local (ie, ocular) complement factor H (CFH) and choroidal neovascularization (CNV) associated with wet age-related macular degeneration (AMD), a leading cause of irreversible blindness, in laser-treated C57BL/6 mice. Immunohistochemical and RT-PCR analysis of retinal pigmented epithelium (RPE)-choroid sclera revealed that the expression of CFH was down-regulated on day 1 with a dramatic increase on days 5 and 7 postlaser injury. Flat mount and Western blot analysis further revealed that membrane attack complex (MAC) expression was up-regulated on days 1 and 3 postlaser injury; however, MAC was down-regulated on days 5 and 7 postinjury but was still higher than in non-injured mice. Similar patterns for CFH and MAC were observed for RPE cells when serial paraffin sections of the laser spots were analyzed. Subretinal injection of siRNA directed against CFH resulted in a threefold suppression of CFH in the RPE and choroid without affecting either CFH levels in the liver or the functional activity of the alternative pathway in the peripheral blood. Ocular knock-down of CFH resulted in increased MAC deposition, which leads to the early onset as well as exacerbation of laser-induced CNV. In conclusion, our findings provide evidence that CFH present on RPE and choroid regulates local MAC formation that is critical for the development of laser-induced CNV.
Lyzogubov
Valeriy V
VV
Department of Ophthalmology, Jones Eye Institute, Pat & Willard Walker Eye Research Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Tytarenko
Ruslana G
RG
Jha
Purushottam
P
Liu
Juan
J
Bora
Nalini S
NS
Bora
Puran S
PS
D000818:Animals; D015153:Blotting, Western; D020256:Choroidal Neovascularization / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D017242:Complement Factor H / Q000037:antagonists & inhibitors / Q000502:physiology*; D004195:Disease Models, Animal; D007124:Immunoenzyme Techniques; D007834:Lasers / Q000009:adverse effects*; D008268:Macular Degeneration / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010857:Pigment Epithelium of Eye / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014785:Vision, Ocular / Q000502:physiology
D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017242:Complement Factor H
J Immunol. 2006 Jun 15;176(12):7221-31
16751365
Br Med Bull. 2008;85:127-49
18334518
Mol Immunol. 2008 Jun;45(11):3125-32
18452991
Arch Ophthalmol. 2004 Apr;122(4):564-72
15078675
J Immunol. 2007 Mar 15;178(6):3831-6
17339482
Semin Immunopathol. 2008 Apr;30(2):85-95
18299835
Invest Ophthalmol Vis Sci. 2008 Nov;49(11):5118-25
18515569
PLoS One. 2008 Jul 02;3(7):e2593
18596911
Proc Natl Acad Sci U S A. 2005 May 17;102(20):7227-32
15870199
Mol Cell Proteomics. 2009 Jun;8(6):1338-49
19202148
Mol Immunol. 2007 Jul;44(13):3398-406
17399790
Science. 2005 Apr 15;308(5720):385-9
15761122
Mol Immunol. 2004 Jun;41(4):355-67
15163532
J Immunol. 2006 Aug 1;177(3):1872-8
16849499
Exp Eye Res. 2000 Nov;71(5):523-33
11040088
Surv Ophthalmol. 2006 Jul-Aug;51(4):316-63
16818082
J Biol Chem. 1988 Nov 15;263(32):16720-4
2972715
Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2679-84
12589025
J Cell Physiol. 2000 Sep;184(3):301-10
10911360
Invest Ophthalmol Vis Sci. 1990 May;31(5):899-908
1692312
J Immunol. 2008 Dec 1;181(11):8068-76
19017999
Invest Ophthalmol Vis Sci. 2009 Jul;50(7):3056-64
19264882
Graefes Arch Clin Exp Ophthalmol. 2007 Nov;245(11):1713-6
17704937
Cell Biol Int. 2009 Jul;33(7):765-71
19422927
Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2328-33
16452172
FEBS J. 2006 Apr;273(7):1403-14
16689928
J Immunol. 2005 Jan 1;174(1):491-7
15611275
Mol Immunol. 2007 Sep;44(16):3901-8
17768108
Eur J Histochem. 2007 Jan-Mar;51(1):59-66
17548270
Invest Ophthalmol Vis Sci. 2006 Sep;47(9):4091-7
16936129
Invest Ophthalmol Vis Sci. 2000 Oct;41(11):3492-502
11006244
Ann N Y Acad Sci. 2007 Aug;1109:93-105
17785294
Exp Eye Res. 2007 Apr;84(4):635-45
17292886
FEBS Lett. 2008 Oct 15;582(23-24):3451-8
18789935
FEBS Lett. 2007 May 15;581(10):1977-82
17466298
Science. 2005 Apr 15;308(5720):421-4
15761121
Ann Med. 2006;38(7):450-71
17101537
Vaccine. 2008 Dec 30;26 Suppl 8:I67-74
19388168
BMC Cell Biol. 2008 Mar 19;9:13
18366689
Lancet. 2008 Nov 22;372(9652):1835-45
19027484
Mol Immunol. 2001 Aug;38(2-3):231-9
11532284
Surv Ophthalmol. 2006 Mar-Apr;51(2):137-52
16500214
J Immunol. 2007 Feb 1;178(3):1783-90
17237428
Am J Pathol. 2009 Jul;175(1):412-21
19541934