Erianin inhibits high glucose-induced retinal angiogenesis via blocking ERK1/2-regulated HIF-1α-VEGF/VEGFR2 signaling pathway.
Erianin is a natural compound found in Dendrobium chrysotoxum Lindl. Diabetic retinopathy (DR) is a serious and common microvascular complication of diabetes. This study aims to investigate the inhibitory mechanism of erianin on retinal neoangiogenesis and its contribution to the amelioration of DR. Erianin blocked high glucose (HG)-induced tube formation and migration in choroid-retinal endothelial RF/6A cells. Erianin inhibited HG-induced vascular endothelial growth factor (VEGF) expression, hypoxia-inducible factor 1-alpha (HIF-1α) translocation into nucleus and ERK1/2 activation in RF/6A and microglia BV-2 cells. MEK1/2 inhibitor U0126 blocked HG-induced HIF-1α and ERK1/2 activation in both above two cells. In addition, erianin abrogated VEGF-induced angiogenesis in vitro and in vivo, and also inhibited VEGF-induced activation of VEGF receptor 2 (VEGFR2) and its downstream cRaf-MEK1/2-ERK1/2 and PI3K-AKT signaling pathways in RF/6A cells. Furthermore, erianin reduced the increased retinal vessels, VEGF expression and microglia activation in streptozotocin (STZ)-induced hyperglycemic and oxygen-induced retinopathy (OIR) mice. In conclusion, our results demonstrate that erianin inhibits retinal neoangiogenesis by abrogating HG-induced VEGF expression by blocking ERK1/2-mediated HIF-1α activation in retinal endothelial and microglial cells, and further suppressing VEGF-induced activation of VEGFR2 and its downstream signals in retinal endothelial cells.
The Shanghai Key Laboratory of Complex Prescription, MOE Key Laboratory for Standardization of Chinese Medicines, and SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Zengyang
Z
Yu
The Shanghai Key Laboratory of Complex Prescription, MOE Key Laboratory for Standardization of Chinese Medicines, and SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Tianyu
T
Zhang
The Shanghai Key Laboratory of Complex Prescription, MOE Key Laboratory for Standardization of Chinese Medicines, and SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Chenyuan
C
Gong
Center for Drug Safety Evaluation and Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Yuchen
Y
Sheng
The Shanghai Key Laboratory of Complex Prescription, MOE Key Laboratory for Standardization of Chinese Medicines, and SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Bin
B
Lu
The Shanghai Key Laboratory of Complex Prescription, MOE Key Laboratory for Standardization of Chinese Medicines, and SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Lingyu
L
Zhou
The Shanghai Key Laboratory of Complex Prescription, MOE Key Laboratory for Standardization of Chinese Medicines, and SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Lili
L
Ji
The Shanghai Key Laboratory of Complex Prescription, MOE Key Laboratory for Standardization of Chinese Medicines, and SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Zhengtao
Z
Wang
J Intern Med. 2013 Feb;273(2):114-27
23216836
World J Diabetes. 2015 Jun 10;6(5):726-33
26069721
J Pathol. 2005 Mar;205(4):530-6
15714461
Invest Ophthalmol Vis Sci. 1997 Jan;38(1):36-47
9008628
J Clin Invest. 1997 May 1;99(9):2192-202
9151791
J Diabetes Res. 2015;2015:518317
25685822
Cell. 2007 Aug 24;130(4):691-703
17719546
J Ophthalmol. 2012;2012:209538
22272370
Ophthalmology. 2003 Sep;110(9):1677-82
13129861
Mol Vis. 2014 Mar 03;20:259-69
24623968
Graefes Arch Clin Exp Ophthalmol. 2015 Apr;253(4):519-25
25023148
Am J Pathol. 1999 Aug;155(2):421-8
10433935
Biochem Soc Trans. 2003 Dec;31(Pt 6):1171-7
14641020
J Biochem Mol Biol. 2003 Jan 31;36(1):120-7
12542982
Curr Pharm Biotechnol. 2011 Mar 1;12(3):369-72
20939797
Int J Ophthalmol. 2013 Oct 18;6(5):573-7
24195027
Clin Ophthalmol. 2012;6:185-91
22331976
J Ophthalmol. 2014;2014:705783
25258680
Biochem Pharmacol. 2013 Dec 1;86(11):1603-13
24076420
Biochim Biophys Acta. 2015 Apr;1850(4):824-31
25641276
J Histochem Cytochem. 2007 Jul;55(7):687-700
17341475
Prog Biophys Mol Biol. 1999;71(3-4):479-500
10354710
Pharmacol Res. 2015 Sep;99:137-48
26054568
Curr Pharm Des. 2005;11(18):2367-81
16022672
Exp Eye Res. 2014 Dec;129:161-71
25304218
Diabetes Care. 2014 Apr;37(4):893-9
24652720
J Cardiovasc Pharmacol. 2014 Sep;64(3):218-27
25192544
Biochem Pharmacol. 2012 Jul 1;84(1):88-92
22484312
Lancet. 2010 Jul 10;376(9735):124-36
20580421
Graefes Arch Clin Exp Ophthalmol. 2010 Jul;248(7):915-30
20174816
Diabetes Technol Ther. 2014 Apr;16(4):224-34
24279470
Invest Ophthalmol Vis Sci. 2009 Apr;50(4):1873-9
19098317
Eur J Cancer. 2004 Jul;40(10):1554-65
15196540
Toxicol Sci. 2012 Jan;125(1):10-9
21984483
Prog Retin Eye Res. 2007 Jan;26(1):1-37
17074526
Mol Cell Biochem. 2010 Oct;343(1-2):27-35
20524146
Biochem Pharmacol. 2015 Aug 1;96(3):278-87
26056075
Exp Eye Res. 2005 May;80(5):651-62
15862172
Vascul Pharmacol. 2014 Sep;62(3):134-42
24846859
Prog Retin Eye Res. 2011 Sep;30(5):343-58
21635964
J Biochem. 2013 Jan;153(1):13-9
23172303
Diabetes Care. 2012 Mar;35(3):556-64
22301125
PLoS One. 2011;6(9):e25213
21980400