Research status and progress of hypoxia-inducible factor on the regulation of diabetic retinopathy_Chinese Journal of Ocular Fundus Diseases

Authors：

He Mengxia ^1,2 , Xie Jie ¹ ,  Meng Qianli ¹

1. Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Eye Institute, Guangdong Academy of Medical Sciences, Guangzhou 510080, China;
2. School of Medicine, South China University of Technology, Guangzhou 510006, China;

Corresponding author：

Meng Qianli, Email: mengqly@163.com

Keywords：

Diabetic retinopathy; Hypoxia-inducible factor 1, alpha subunit; Vascular endothelial growth factors; Review

DOI：

10.3760/cma.j.cn511434-20200609-00268

Video：

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The intervention therapy targeting vascular endothelial growth factor (VEGF) has become a specific and effective method for the treatment of diabetic retinopathy (DR). However, some patients did not respond or responded poorly to anti-VEGF therapy, and its effects of eliminating edema and improving vision appear to be unstable in the same patient. Hypoxia-inducible factor-1α (HIF-1α), an important upstream transcriptional regulator of VEGF, is an oxygen concentration-sensitive protein expressed in tissues under hypoxia. It can simultaneously target many downstream target genes except VEGF, such as placental growth factor and angiopoietin-like protein 4, to cause blood-retinal barrier damage and neovascularization, and thus participate in various pathological changes of DR to promote the occurrence and development of DR. Therefore, direct intervention of HIF-1α or targeting one or more downstream target genes regulated by HIF-1α to treat DR may have better efficacy. In the future, the development of effective and safe HIF inhibitors or anti-VEGF with HIF-1α other target gene inhibitors may have broader clinical application prospects.

Citation： He Mengxia, Xie Jie, Meng Qianli. Research status and progress of hypoxia-inducible factor on the regulation of diabetic retinopathy. Chinese Journal of Ocular Fundus Diseases, 2021, 37(8): 661-664. doi: 10.3760/cma.j.cn511434-20200609-00268 Copy

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2.	Peet DJ, Kittipassorn T, Wood JP, et al. HIF signalling: the eyes have it[J]. Exp Cell Res, 2017, 356(2): 136-140. DOI: 10.1016/j.yexcr.2017.03.030.
3.	Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis[J]. Nature, 2011, 473(7347): 298-307. DOI: 10.1038/nature10144.
4.	Subhani S, Vavilala DT, Mukherji M. HIF inhibitors for ischemic retinopathies and cancers: optionsbeyond anti-VEGF therapies[J]. Angiogenesis, 2016, 19(3): 257-273. DOI: 10.1007/s10456-016-9510-0.
5.	Choudhry H, Harris AL. Advances in hypoxia-inducible factor biology[J]. Cell Metab, 2018, 27(2): 281-298. DOI: 10.1016/j.cmet.2017.10.005.
6.	Kaelin WG Jr, Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway[J]. Mol Cell, 2008, 30(4): 393-402. DOI: 10.1016/j.molcel.2008.04.009.
7.	Smythies JA, Sun M, Masson N, et al. Inherent DNA-binding specificities of the HIF-1α and HIF-2α transcription factors in chromatin[J/OL]. Embo Rep, 2019, 20(1): e46401[2018-11-14]. https://pubmed.ncbi.nlm.nih.gov/30429208/. DOI: 10.15252/embr.201846401.
8.	Gonzalez FJ, Xie C, Jiang C. The role of hypoxia-inducible factors in metabolic diseases[J]. Nat Rev Endocrinol, 2018, 15(1): 21-32. DOI: 10.1038/s41574-018-0096-z.
9.	Semenza GL. Hypoxia-inducible factors in physiology and medicine[J]. Cell, 2012, 148(3): 399-408. DOI: 10.1016/j.cell.2012.01.021.
10.	Ravenna L, Salvatori L, Russo MA. HIF3α: the little we know[J]. FEBS J, 2016, 283(6): 993-1003. DOI: 10.1111/febs.13572.
11.	Cummins EP, Keogh CE, Crean D, et al. The role of HIF in immunity and inflammation[J]. Mol Aspects Med, 2016, 47-48: 24-34. DOI: 10.1016/j.mam.2015.12.004.
12.	Taylor CT, Colgan SP. Regulation of immunity and inflammation by hypoxia in immunological niches[J]. Nat Rev Immunol, 2017, 17(12): 774-785. DOI: 10.1038/nri.2017.103.
13.	Watts ER, Walmsley SR. Inflammation and hypoxia: HIF and PHD isoform selectivity[J]. Trends Mol Med, 2019, 25(1): 33-46. DOI: 10.1016/j.molmed.2018.10.006.
14.	Yadav AK, Yadav PK, Chaudhary GR, et al. Autophagy in hypoxic ovary[J]. Cell Mol Life Sci, 2019, 76(17): 3311-3322. DOI: 10.1007/s00018-019-03122-4.
15.	Lee KE, Simon MC. SnapShot: hypoxia-inducible factors[J]. Cell, 2015, 163(5): 1288. DOI: 10.1016/j.cell.2015.11.011.
16.	Whitehead M, Wickremasinghe S, Osborne A, et al. Diabetic retinopathy: a complex pathophysiology requiring novel therapeutic strategies[J]. Expert Opin Biol Ther, 2018, 18(12): 1257-1270. DOI: 10.1080/14712598.2018.1545836.
17.	Campochiaro PA. Molecular pathogenesis of retinal and choroidal vascular diseases[J]. Prog Retin Eye Res, 2015, 49: 67-81. DOI: 10.1016/j.preteyeres.2015.06.002.
18.	Lu Q, Lu P, Chen W, et al. ANGPTL-4 induces diabetic retinal inflammation by activating Profilin-1[J]. Exp Eye Res, 2018, 166: 140-150. DOI: 10.1016/j.exer.2017.10.009.
19.	Wang W, Lo ACY. Diabetic retinopathy: pathophysiology and treatments[J/OL]. Int J Mol Sci, 2018, 19(6): 1816[2018-06-20]. https://pubmed.ncbi.nlm.nih.gov/29925789/. DOI: 10.3390/ijms19061816.
20.	Zhang C, Xie H, Yang Q, et al. Erythropoietin protects outer blood-retinal barrier in experimental diabetic retinopathy by up-regulating ZO-1 and occludin[J]. Clin Exp Ophthalmol, 2019, 47(9): 1182-1197. DOI: 10.1111/ceo.13619.
21.	D'Amico AG, Maugeri G, Bucolo C, et al. Nap interferes with hypoxia-inducible factors and VEGF expression in retina of diabetic rats[J]. J Mol Neurosci, 2017, 61(2): 256-266. DOI: 10.1007/s12031-016-0869-6.
22.	D'Amico AG, Maugeri G, Rasà D, et al. NAP modulates hyperglycemic-inflammatory event of diabetic retina by counteracting outer blood retinal barrier damage[J]. J Cell Physiol, 2019, 234(4): 5230-5240. DOI: 10.1002/jcp.27331.
23.	Wei J, Jiang H, Gao H, et al. Blocking mammalian target of rapamycin (mTOR) attenuates HIF-1α pathways engaged-vascular endothelial growth factor (VEGF) in diabetic retinopathy[J]. Cell Physiol Biochem, 2016, 40(6): 1570-1577. DOI: 10.1159/000453207.
24.	Huang H, He J, Johnson D, et al. Deletion of placental growth factor prevents diabetic retinopathy and is associated with Akt activation and HIF1α-VEGF pathway inhibition[J]. Diabetes, 2015, 64: 200-212. DOI: 10.2337/db15-er03.
25.	Gong Q, Xie J, Li Y, et al. Enhanced ROBO4 is mediated by up-regulation of HIF-1α/SP1 or reduction in miR-125b-5p/miR-146a-5p in diabetic retinopathy[J]. J Cell Mol Med, 2019, 23(7): 4723-4737. DOI: 10.1111/jcmm.14369.
26.	Kurihara T, Westenskow PD, Friedlander M. Hypoxia-inducible factor (HIF)/vascular endothelial growth factor (VEGF) signaling in the retina[J]. Adv Exp Med Biol, 2014, 801: 275-281. DOI: 10.1007/978-1-4614-3209-8_35.
27.	Olivares AM, Althoff K, Chen GF, et al. Animal models of diabetic retinopathy[J/OL]. Curr Diab Rep, 2017, 17(10): 93[2017-08-24]. https://pubmed.ncbi.nlm.nih.gov/28836097/. DOI: 10.1007/s11892-017-0913-0.
28.	Mowat FM, Luhmann UF, Smith AJ, et al. HIF-1alpha and HIF-2alpha are differentially activated in distinct cell populations in retinal ischaemia[J/OL]. PLoS One, 2010, 5(6): e11103[2010-6-14]. https://pubmed.ncbi.nlm.nih.gov/20559438/. DOI: 10.1371/journal.pone.0011103.
29.	Zeng M, Shen J, Liu Y, et al. The HIF-1 antagonist acriflavine: visualization in retina and suppression of ocular neovascularization[J]. J Mol Med (Berl), 2017, 95(4): 417-429. DOI: 10.1007/s00109-016-1498-9.
30.	Han N, Xu H, Yu N, et al. MiR-203a-3p inhibits retinal angiogenesis and alleviates proliferative diabetic retinopathy in oxygen-induced retinopathy (OIR) rat model via targeting VEGFA and HIF-1α[J]. Clin Exp Pharmacol Physiol, 2020, 47(1): 85-94. DOI: 10.1111/1440-1681.13163.
31.	Yu Z, Zhang T, Gong C, et al. Erianin inhibits high glucose-induced retinal angiogenesis via blocking ERK1/2-regulated HIF-1α-VEGF/VEGFR2 signaling pathway[J/OL]. Sci Rep, 2016, 6: 34306[2016-09-28]. https://pubmed.ncbi.nlm.nih.gov/27678303/. DOI: 10.1038/srep34306.
32.	Miwa Y, Hoshino Y, Shoda C, et al. Pharmacological HIF inhibition prevents retinal neovascularization with improved visual function in a murine oxygen-induced retinopathy model[J]. Neurochem Int, 2019, 128: 21-31. DOI: 10.1016/j.neuint.2019.03.008.
33.	Schmidt-Erfurth U, Garcia-Arumi J, Bandello F, et al. Guidelines for the management of diabetic macular edema by the European Society of Retina Specialists (EURETINA)[J]. Ophthalmologica, 2017, 237(4): 185-222. DOI: 10.1159/000458539.
34.	Yang X, Cao J, Du Y, et al. Angiopoietin-like protein 4 (ANGPTL4) induces retinal pigment epithelial barrier breakdown by activating signal transducer and activator of transcription 3 (STAT3): evidence from ARPE-19 cells under hypoxic condition and diabetic rats[J]. Med Sci Monit, 2019, 25: 6742-6754. DOI: 10.12659/MSM.915748.
35.	Sodhi A, Ma T, Menon D, et al. Angiopoietin-like 4 binds neuropilins and cooperates with VEGF to induce diabetic macular edema[J]. J Clin Invest, 2019, 129(11): 4593-4608. DOI: 10.1172/JCI120879.
36.	Maugeri G, D'Amico AG, Saccone S, et al. PACAP and VIP inhibit HIF-1α-mediated VEGF expression in a model of diabetic macular edema[J]. J Cell Physiol, 2017, 232(5): 1209-1215. DOI: 10.1002/jcp.25616.
37.	Maugeri G, D'Amico AG, Rasà DM, et al. Nicotine promotes blood retinal barrier damage in a model of human diabetic macular edema[J]. Toxicol In Vitro, 2017, 44: 182-189. DOI: 10.1016/j.tiv.2017.07.003.

1. Wong TY, Sun J, Kawasaki R, et al. Guidelines on diabetic eye care: the international council of ophthalmology recommendations for screening, follow-up, referral, and treatment based on resource settings[J]. Ophthalmology, 2018, 125(10): 1608-1622. DOI: 10.1016/j.ophtha.2018.04.007.
2. Peet DJ, Kittipassorn T, Wood JP, et al. HIF signalling: the eyes have it[J]. Exp Cell Res, 2017, 356(2): 136-140. DOI: 10.1016/j.yexcr.2017.03.030.
3. Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis[J]. Nature, 2011, 473(7347): 298-307. DOI: 10.1038/nature10144.
4. Subhani S, Vavilala DT, Mukherji M. HIF inhibitors for ischemic retinopathies and cancers: optionsbeyond anti-VEGF therapies[J]. Angiogenesis, 2016, 19(3): 257-273. DOI: 10.1007/s10456-016-9510-0.
5. Choudhry H, Harris AL. Advances in hypoxia-inducible factor biology[J]. Cell Metab, 2018, 27(2): 281-298. DOI: 10.1016/j.cmet.2017.10.005.
6. Kaelin WG Jr, Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway[J]. Mol Cell, 2008, 30(4): 393-402. DOI: 10.1016/j.molcel.2008.04.009.
7. Smythies JA, Sun M, Masson N, et al. Inherent DNA-binding specificities of the HIF-1α and HIF-2α transcription factors in chromatin[J/OL]. Embo Rep, 2019, 20(1): e46401[2018-11-14]. https://pubmed.ncbi.nlm.nih.gov/30429208/. DOI: 10.15252/embr.201846401.
8. Gonzalez FJ, Xie C, Jiang C. The role of hypoxia-inducible factors in metabolic diseases[J]. Nat Rev Endocrinol, 2018, 15(1): 21-32. DOI: 10.1038/s41574-018-0096-z.
9. Semenza GL. Hypoxia-inducible factors in physiology and medicine[J]. Cell, 2012, 148(3): 399-408. DOI: 10.1016/j.cell.2012.01.021.
10. Ravenna L, Salvatori L, Russo MA. HIF3α: the little we know[J]. FEBS J, 2016, 283(6): 993-1003. DOI: 10.1111/febs.13572.
11. Cummins EP, Keogh CE, Crean D, et al. The role of HIF in immunity and inflammation[J]. Mol Aspects Med, 2016, 47-48: 24-34. DOI: 10.1016/j.mam.2015.12.004.
12. Taylor CT, Colgan SP. Regulation of immunity and inflammation by hypoxia in immunological niches[J]. Nat Rev Immunol, 2017, 17(12): 774-785. DOI: 10.1038/nri.2017.103.
13. Watts ER, Walmsley SR. Inflammation and hypoxia: HIF and PHD isoform selectivity[J]. Trends Mol Med, 2019, 25(1): 33-46. DOI: 10.1016/j.molmed.2018.10.006.
14. Yadav AK, Yadav PK, Chaudhary GR, et al. Autophagy in hypoxic ovary[J]. Cell Mol Life Sci, 2019, 76(17): 3311-3322. DOI: 10.1007/s00018-019-03122-4.
15. Lee KE, Simon MC. SnapShot: hypoxia-inducible factors[J]. Cell, 2015, 163(5): 1288. DOI: 10.1016/j.cell.2015.11.011.
16. Whitehead M, Wickremasinghe S, Osborne A, et al. Diabetic retinopathy: a complex pathophysiology requiring novel therapeutic strategies[J]. Expert Opin Biol Ther, 2018, 18(12): 1257-1270. DOI: 10.1080/14712598.2018.1545836.
17. Campochiaro PA. Molecular pathogenesis of retinal and choroidal vascular diseases[J]. Prog Retin Eye Res, 2015, 49: 67-81. DOI: 10.1016/j.preteyeres.2015.06.002.
18. Lu Q, Lu P, Chen W, et al. ANGPTL-4 induces diabetic retinal inflammation by activating Profilin-1[J]. Exp Eye Res, 2018, 166: 140-150. DOI: 10.1016/j.exer.2017.10.009.
19. Wang W, Lo ACY. Diabetic retinopathy: pathophysiology and treatments[J/OL]. Int J Mol Sci, 2018, 19(6): 1816[2018-06-20]. https://pubmed.ncbi.nlm.nih.gov/29925789/. DOI: 10.3390/ijms19061816.
20. Zhang C, Xie H, Yang Q, et al. Erythropoietin protects outer blood-retinal barrier in experimental diabetic retinopathy by up-regulating ZO-1 and occludin[J]. Clin Exp Ophthalmol, 2019, 47(9): 1182-1197. DOI: 10.1111/ceo.13619.
21. D'Amico AG, Maugeri G, Bucolo C, et al. Nap interferes with hypoxia-inducible factors and VEGF expression in retina of diabetic rats[J]. J Mol Neurosci, 2017, 61(2): 256-266. DOI: 10.1007/s12031-016-0869-6.
22. D'Amico AG, Maugeri G, Rasà D, et al. NAP modulates hyperglycemic-inflammatory event of diabetic retina by counteracting outer blood retinal barrier damage[J]. J Cell Physiol, 2019, 234(4): 5230-5240. DOI: 10.1002/jcp.27331.
23. Wei J, Jiang H, Gao H, et al. Blocking mammalian target of rapamycin (mTOR) attenuates HIF-1α pathways engaged-vascular endothelial growth factor (VEGF) in diabetic retinopathy[J]. Cell Physiol Biochem, 2016, 40(6): 1570-1577. DOI: 10.1159/000453207.
24. Huang H, He J, Johnson D, et al. Deletion of placental growth factor prevents diabetic retinopathy and is associated with Akt activation and HIF1α-VEGF pathway inhibition[J]. Diabetes, 2015, 64: 200-212. DOI: 10.2337/db15-er03.
25. Gong Q, Xie J, Li Y, et al. Enhanced ROBO4 is mediated by up-regulation of HIF-1α/SP1 or reduction in miR-125b-5p/miR-146a-5p in diabetic retinopathy[J]. J Cell Mol Med, 2019, 23(7): 4723-4737. DOI: 10.1111/jcmm.14369.
26. Kurihara T, Westenskow PD, Friedlander M. Hypoxia-inducible factor (HIF)/vascular endothelial growth factor (VEGF) signaling in the retina[J]. Adv Exp Med Biol, 2014, 801: 275-281. DOI: 10.1007/978-1-4614-3209-8_35.
27. Olivares AM, Althoff K, Chen GF, et al. Animal models of diabetic retinopathy[J/OL]. Curr Diab Rep, 2017, 17(10): 93[2017-08-24]. https://pubmed.ncbi.nlm.nih.gov/28836097/. DOI: 10.1007/s11892-017-0913-0.
28. Mowat FM, Luhmann UF, Smith AJ, et al. HIF-1alpha and HIF-2alpha are differentially activated in distinct cell populations in retinal ischaemia[J/OL]. PLoS One, 2010, 5(6): e11103[2010-6-14]. https://pubmed.ncbi.nlm.nih.gov/20559438/. DOI: 10.1371/journal.pone.0011103.
29. Zeng M, Shen J, Liu Y, et al. The HIF-1 antagonist acriflavine: visualization in retina and suppression of ocular neovascularization[J]. J Mol Med (Berl), 2017, 95(4): 417-429. DOI: 10.1007/s00109-016-1498-9.
30. Han N, Xu H, Yu N, et al. MiR-203a-3p inhibits retinal angiogenesis and alleviates proliferative diabetic retinopathy in oxygen-induced retinopathy (OIR) rat model via targeting VEGFA and HIF-1α[J]. Clin Exp Pharmacol Physiol, 2020, 47(1): 85-94. DOI: 10.1111/1440-1681.13163.
31. Yu Z, Zhang T, Gong C, et al. Erianin inhibits high glucose-induced retinal angiogenesis via blocking ERK1/2-regulated HIF-1α-VEGF/VEGFR2 signaling pathway[J/OL]. Sci Rep, 2016, 6: 34306[2016-09-28]. https://pubmed.ncbi.nlm.nih.gov/27678303/. DOI: 10.1038/srep34306.
32. Miwa Y, Hoshino Y, Shoda C, et al. Pharmacological HIF inhibition prevents retinal neovascularization with improved visual function in a murine oxygen-induced retinopathy model[J]. Neurochem Int, 2019, 128: 21-31. DOI: 10.1016/j.neuint.2019.03.008.
33. Schmidt-Erfurth U, Garcia-Arumi J, Bandello F, et al. Guidelines for the management of diabetic macular edema by the European Society of Retina Specialists (EURETINA)[J]. Ophthalmologica, 2017, 237(4): 185-222. DOI: 10.1159/000458539.
34. Yang X, Cao J, Du Y, et al. Angiopoietin-like protein 4 (ANGPTL4) induces retinal pigment epithelial barrier breakdown by activating signal transducer and activator of transcription 3 (STAT3): evidence from ARPE-19 cells under hypoxic condition and diabetic rats[J]. Med Sci Monit, 2019, 25: 6742-6754. DOI: 10.12659/MSM.915748.
35. Sodhi A, Ma T, Menon D, et al. Angiopoietin-like 4 binds neuropilins and cooperates with VEGF to induce diabetic macular edema[J]. J Clin Invest, 2019, 129(11): 4593-4608. DOI: 10.1172/JCI120879.
36. Maugeri G, D'Amico AG, Saccone S, et al. PACAP and VIP inhibit HIF-1α-mediated VEGF expression in a model of diabetic macular edema[J]. J Cell Physiol, 2017, 232(5): 1209-1215. DOI: 10.1002/jcp.25616.
37. Maugeri G, D'Amico AG, Rasà DM, et al. Nicotine promotes blood retinal barrier damage in a model of human diabetic macular edema[J]. Toxicol In Vitro, 2017, 44: 182-189. DOI: 10.1016/j.tiv.2017.07.003.

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Research status and progress of hypoxia-inducible factor on the regulation of diabetic retinopathy

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