The role of Raf-1 kinase in diabetic retinopathy.
Many metabolic pathways, including oxidative stress, PKC and the polyol pathway have been implicated in the development of diabetic retinopathy, but despite extensive research, its pathogenesis remains unclear. Recent studies have shown the role of a low-molecular-weight GTP-binding protein (H-Ras)-mediated signaling pathway in its development. The key effector protein of Ras function is a threonine/serine kinase-Raf kinase, and this kinase is involved in a variety of functions, including the cell cycle and proliferation and apoptosis. In animal models of diabetic retinopathy, Raf kinase is activated in the retina and its microvasculature. Activated Raf kinase is associated with increased apoptosis of retinal capillary cells, the process that precedes the development of retinal histopathology, and inhibition of Raf kinase ameliorates apoptosis. In clinical settings, inhibitors of Raf kinase have shown promising results in cancer treatment, and Raf kinase antisense oligonucleotides, iCo 007, is now in Phase II trial for macular edema, a chronic ocular disease associated with retinal neovascularization. Further elucidating the role of Raf kinase in diabetic retinopathy, and advances in the generation of antisense therapy for chronic diseases, should help test Raf antisense oligonucleotides for the treatment of this blinding complication that diabetic patients fear the most.
Ghulam
G
Mohammad
Renu A
RA
Kowluru
D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005123:Eye / Q000503:physiopathology; D006801:Humans; D020935:MAP Kinase Signaling System; D058990:Molecular Targeted Therapy; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000201:enzymology; D012171:Retinal Vessels / Q000201:enzymology; D015398:Signal Transduction
D004791:Enzyme Inhibitors; D019908:Proto-Oncogene Proteins c-raf
Diabetes. 2003 May;52(5):1229-34
12716757
Biochim Biophys Acta. 2007 Aug;1773(8):1263-84
17126425
Expert Opin Emerg Drugs. 2010 Jun;15(2):203-23
20151845
J Diabetes Sci Technol. 2009 Jul 01;3(4):924-30
20144342
Diabetes. 1989 Oct;38(10):1203-6
2676655
J Immunol. 1996 Dec 15;157(12):5277-83
8955173
Circ Res. 2010 Apr 30;106(8):1319-31
20431074
Diabetes Care. 1993 Apr;16(4):642-52
8462395
Diabetes. 2004 Dec;53(12):3233-8
15561955
Exp Diabetes Res. 2007;2007:95103
18274606
Invest Ophthalmol Vis Sci. 2000 Nov;41(12):3972-8
11053301
Cell Mol Life Sci. 2011 Mar;68(6):1079-90
20803231
Future Oncol. 2010 May;6(5):655-63
20465381
Arch Ophthalmol. 1998 Jul;116(7):874-86
9682700
FEBS J. 2009 Apr;276(7):1817-25
19243428
Lancet. 1998 Sep 12;352(9131):837-53
9742976
Am J Obstet Gynecol. 2006 Feb;194(2):580-5
16458664
Int J Biochem Cell Biol. 2008;40(12):2707-19
18562239
Immunology. 1999 May;97(1):26-35
10447711
Am J Pathol. 2002 May;160(5):1683-93
12000720
Carcinogenesis. 2004 May;25(5):647-59
14688022
J Biol Chem. 2000 Dec 15;275(50):39435-43
10993883
Invest Ophthalmol Vis Sci. 2010 Apr;51(4):2158-64
20071676
Surgery. 2004 Sep;136(3):708-15
15349122
Sci Signal. 2010 Mar 16;3(113):ra21
20234004
Gynecol Oncol. 2003 Apr;89(1):129-33
12694666
Endocrinology. 2010 Sep;151(9):4455-66
20630999
J Clin Invest. 1996 Jun 15;97(12):2883-90
8675702
Ophthalmic Res. 1997;29(5):354-62
9323726
Diabetes. 1998 Mar;47(3):445-9
9519752
Biochem Biophys Res Commun. 2010 Aug 27;399(3):313-7
20674547
Oncogene. 2010 Sep 30;29(39):5404-15
20603618
Expert Opin Pharmacother. 2001 Feb;2(2):277-91
11336586
Invest Ophthalmol Vis Sci. 2003 Dec;44(12):5327-34
14638734
Int J Biomed Sci. 2008 Mar;4(1):20-8
23675062
Carcinogenesis. 2006 Aug;27(8):1692-8
16613839
Invest Ophthalmol Vis Sci. 2009 Mar;50(3):1400-7
19029021
Adv Exp Med Biol. 2006;579:227-42
16620022
Free Radic Biol Med. 2002 Apr 15;32(8):688-701
11937295
Curr Med Chem. 2006;13(27):3307-17
17168853
J Clin Invest. 1998 Aug 15;102(4):783-91
9710447
Curr Opin Mol Ther. 2007 Apr;9(2):126-31
17458165
Diabetes. 2004 Mar;53(3):775-83
14988264
Curr Med Chem. 2009;16(1):94-112
19149564
Arch Ophthalmol. 1977 Jul;95(7):1215-20
880082
Diabetes. 2002 Jul;51(7):2241-8
12086956
Eur J Cancer. 1991;27(11):1466-71
1835863
Biochim Biophys Acta. 2007 Aug;1773(8):1196-212
17555829
Diabetologia. 2002 Dec;45(12):1617-34
12488951
J Cell Sci. 2005 Jan 1;118(Pt 1):243-52
15615788
Microvasc Res. 2008 Nov;76(3):189-93
18514235
Diabetes. 2010 Apr;59(4):967-77
20071600
Mol Cell Biochem. 2007 Feb;296(1-2):69-76
16924412
Circulation. 2002 Feb 26;105(8):968-74
11864927
Hosp Med. 2003 Jul;64(7):396-9
12886848
Invest Ophthalmol Vis Sci. 2007 Aug;48(8):3805-11
17652755
J Biol Chem. 1996 Oct 18;271(42):26389-94
8824295
Semin Ophthalmol. 2009 Mar-Apr;24(2):87-92
19373692
Diabetes. 2004 Nov;53(11):2960-7
15504977
Carcinogenesis. 2001 Sep;22(9):1385-92
11532859
Am J Physiol Endocrinol Metab. 2008 Nov;295(5):E1243-54
18796547
Biochem Biophys Res Commun. 2009 Sep 25;387(3):461-6
19607814
Mol Vis. 2007 Apr 19;13:602-10
17515880
Ophthalmology. 1994 Jan;101(1):68-76
8302566
N Engl J Med. 2004 Jan 1;350(1):48-58
14702427
Apoptosis. 2006 Nov;11(11):1933-44
17013754
Free Radic Res. 2003 Nov;37(11):1169-80
14703729
Curr Opin Genet Dev. 2007 Feb;17(1):15-22
17208427
Mitochondrion. 2007 Dec;7(6):367-73
17855174
J Clin Invest. 2005 Oct;115(10):2801-10
16151532
Biochem Biophys Res Commun. 2002 Nov 15;298(5):805-14
12419327
Stroke. 2009 Apr;40(4):1467-73
19228841