Iron overload in diabetic retinopathy: a cause or a consequence of impaired mechanisms?
Iron is an essential ion for life, playing a central role in many metabolic processes. The most important property of free iron is its capacity to be reversibly oxidized and reduced, but at same time this make it highly pro-oxidant molecule. In this regard, iron is able to generate powerful reactive oxygen species (ROS). For this reason, careful control on iron availability is central to the maintenance of normal cell function in the retina. In the diabetic eye there is an impairment of iron homeostasis, thus leading to iron overload. The mechanisms involved in this process include: (1) Destruction of heme molecules induced by hyperglycemia (2) Intraretinal and vitreal hemorrhages (3) Overexpression of the renin-angiotensin system. The main consequences of iron overload are the following: (1) Retinal neurodegeneration due to the increase of oxidative stress (2) Increase of AGE-RAGE binding (3) Defective phagocytosis of retinal pigment epithelium, which generates the accumulation of autoantigens and the synthesis of proinflammatory cytokines. Further studies addressed to explore not only the role of iron in the pathogenesis of diabetic retinopathy, but also to design novel therapeutic strategies based on the regulation of iron homeostasis are needed.
Ciudin
Andreea
A
CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Unidad de Diabetes y Metabolismo, Instituto de Investigación Hospital Universitario Vall d'Hebron, Paseo Vall d'Hebron 119-129, 08035 Barcelona, Spain.
Hernández
Cristina
C
Simó
Rafael
R
D016207:Cytokines / Q000096:biosynthesis; D003930:Diabetic Retinopathy / Q000150:complications*; D006418:Heme / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000502:physiology; D019190:Iron Overload / Q000150:complications*; D018384:Oxidative Stress; D012160:Retina / Q000503:physiopathology; D012166:Retinal Hemorrhage; D055351:Retinal Neurons / Q000502:physiology
D016207:Cytokines; D006418:Heme; D007501:Iron
Exp Eye Res. 1994 Nov;59(5):551-5
9492756
Neurosci Lett. 1996 Feb 16;205(1):13-6
8867009
Diabetes. 1999 Oct;48(10):2074-82
10512376
Curr Diabetes Rev. 2006 Feb;2(1):71-98
18220619
Mol Vis. 2004 Aug 26;10:598-607
15354085
FEBS Lett. 1996 Mar 11;382(1-2):218-9; discussion 220-1
8612757
J Cell Physiol. 1992 Jul;152(1):102-10
1618912
Biol Trace Elem Res. 2002 Winter;90(1-3):15-23
12666821
Ophthalmic Res. 1990;22(3):194-200
2385435
J Biol Chem. 2006 Feb 3;281(5):2835-40
16319067
Int J Dev Neurosci. 1996 Oct;14(6):785-95
8960986
Methods Enzymol. 1990;186:1-85
2172697
Mol Vis. 2008 Aug 15;14:1496-502
18709137
J Clin Endocrinol Metab. 1989 Jan;68(1):160-7
2642484
Am J Physiol Heart Circ Physiol. 2005 Aug;289(2):H522-4
16014614
Curr Drug Targets. 2005 Jun;6(4):511-24
16026270
Nucleic Acids Res. 1999 Nov 1;27(21):4223-7
10518614
Antioxid Redox Signal. 2010 Feb;12(2):233-48
19697995
Biochem Biophys Res Commun. 2008 Mar 7;367(2):413-9
18174022
Neuroreport. 2006 Nov 27;17(17):1803-6
17164668
Exp Diabetes Res. 2007;2007:36150
17713594
Nature. 2000 Feb 17;403(6771):776-81
10693807
Exp Eye Res. 1994 Oct;59(4):441-5
7859819
Diabetologia. 2009 Dec;52(12):2633-41
19823802
Invest Ophthalmol Vis Sci. 2003 Sep;44(9):3732-41
12939286
Photochem Photobiol. 2003 Apr;77(4):440-5
12733656
Curr Eye Res. 1997 Apr;16(4):380-6
9134328
Invest Ophthalmol Vis Sci. 2002 Feb;43(2):537-45
11818402
Eur J Neurosci. 1999 Oct;11(10):3387-94
10564346
Retina. 1999;19(2):141-7
10213241
Nat Genet. 1999 Feb;21(2):195-9
9988272
Invest Ophthalmol Vis Sci. 2000 Jul;41(8):2343-51
10892882
JAMA. 2003 Oct 15;290(15):2057-60
14559961
Neurochem Int. 2001 Apr;38(5):385-90
11222918
Mol Vis. 2008 May 20;14:928-41
18509548
J Biol Chem. 2002 Jun 21;277(25):22430-7
11953424
J Biol Chem. 2000 Jun 30;275(26):19906-12
10747949
Biol Pharm Bull. 2006 Oct;29(10):2148-50
17015969
Invest Ophthalmol Vis Sci. 2006 May;47(5):2135-40
16639025
Invest Ophthalmol Vis Sci. 2009 Apr;50(4):1895-902
19151392
Invest Ophthalmol Vis Sci. 2004 May;45(5):1410-7
15111596
Prog Retin Eye Res. 2007 Nov;26(6):649-73
17921041
Neuroscientist. 2002 Feb;8(1):22-32
11843096
Invest Ophthalmol Vis Sci. 2005 Mar;46(3):1078-84
15728568
Diabetes Care. 2009 Aug;32(8):1556-62
19638526
Prog Retin Eye Res. 2008 Nov;27(6):622-47
18940262
Free Radic Biol Med. 2008 Apr 1;44(7):1286-94
18082149
Diabetes. 2006 Sep;55(9):2401-11
16936187
Diabetologia. 1997 Jun;40(6):629-34
9222640
Am J Pathol. 2003 Sep;163(3):879-87
12937129
J Neurochem. 2000 Jul;75(1):304-13
10854275
J Biol Chem. 1991 May 5;266(13):8002-7
2022630
J Inorg Biochem. 2008 Dec;102(12):2130-5
18835041
J Invest Dermatol. 2003 May;120(5):871-9
12713595
Int J Biochem Cell Biol. 2001 Oct;33(10):940-59
11470229
Free Radic Res. 1999 Dec;31(6):459-75
10630670
Prog Retin Eye Res. 2008 Nov;27(6):596-607
18848639
Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):4924-8
9560204
Biochem J. 2009 Nov 11;424(2):243-52
19715555
Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8175-82
8710843
Invest Ophthalmol Vis Sci. 2007 Dec;48(12):5699-707
18055822
Curr Eye Res. 2003 Nov;27(5):301-8
14562166
Curr Pharm Des. 2008;14(10):962-8
18473846
Biophys Chem. 2003 Sep;105(2-3):743-55
14499930
J Physiol. 2008 Sep 15;586(18):4401-8
18565995
Invest Ophthalmol Vis Sci. 2007 Jan;48(1):438-45
17197565
J Mol Biol. 1994 May 20;238(5):649-54
8182740
Antioxid Redox Signal. 2002 Apr;4(2):229-40
12006174
Invest Ophthalmol Vis Sci. 2008 Jan;49(1):310-9
18172108
Arterioscler Thromb Vasc Biol. 2004 Dec;24(12):2257-62
15486315
Hypertens Res. 2007 Feb;30(2):195-202
17460390
Free Radic Res. 2001 Feb;34(2):189-91
11264895
Indian J Ophthalmol. 2004 Jun;52(2):145-8
15283220
J Clin Invest. 1998 Aug 15;102(4):783-91
9710447
Trends Biochem Sci. 1996 May;21(5):174-7
8871401
Diabetes. 1998 May;47(5):815-20
9588455
Science. 1978 Sep 8;201(4359):875-80
210504
Annu Rev Neurosci. 1989;12:289-327
2467600
Diabetes Care. 2007 Nov;30(11):2902-8
17704349
Graefes Arch Clin Exp Ophthalmol. 1989;227(3):281-6
2472309
Invest Ophthalmol Vis Sci. 1983 Jul;24(7):862-7
6862792
Free Radic Biol Med. 2003 Mar 15;34(6):674-82
12633744
Life Sci. 1998;63(25):2271-84
9870713
J Proteome Res. 2008 Jun;7(6):2516-25
18433156
J Biol Chem. 1966 Nov 10;241(21):5053-9
5925868
Blood. 2005 Jun 15;105(12):4613-9
15741220
Retina. 2007 Oct;27(8):997-1003
18040235
Ophthalmic Res. 2000 Mar-Jun;32(2-3):61-8
10754436
Rev Endocr Metab Disord. 2008 Dec;9(4):315-27
18654858
Ophthalmologica. 1975;170(1):72-83
806863
Invest Ophthalmol Vis Sci. 2010 Sep;51(9):4416-21
20375324
Biochem Biophys Res Commun. 1998 Jan 6;242(1):39-45
9439606
Arch Ophthalmol. 1997 Sep;115(9):1161-6
9298058
Nat Med. 1999 Jun;5(6):620-1
10371497
Am J Physiol Cell Physiol. 2003 Feb;284(2):C263-72
12388107
Proc Natl Acad Sci U S A. 2004 Sep 21;101(38):13850-5
15365174
Ophthalmic Physiol Opt. 2003 Nov;23(6):495-501
14622351
FEBS Lett. 2003 Feb 27;537(1-3):187-92
12606055
Ann N Y Acad Sci. 2004 Mar;1012:179-82
15105265
Int J Biochem Cell Biol. 2006;38(5-6):752-65
16165393
Curr Med Chem. 2009;16(1):113-29
19149565
Blood Cells Mol Dis. 2002 Nov-Dec;29(3):376-83
12547228
Invest Ophthalmol Vis Sci. 2009 Mar;50(3):1440-7
19182262
J Biol Chem. 1995 Sep 15;270(37):21645-51
7665579
J Biol Chem. 1997 Aug 8;272(32):20185-90
9242695
Exp Eye Res. 2009 Feb;88(2):204-15
19059397
Exp Diabetes Res. 2007;2007:43603
17641741