糖尿病周围神经病变是糖尿病最常见的慢性并发症之一。缺血、缺氧在糖尿病周围神经病变中起着重要作用，而缺氧可刺激缺氧诱导因子（HIF）-1α表达增强。HIF-1α可增强细胞对低氧的适应能力，对多种细胞具有保护作用，亦可直接抑制神经细胞凋亡以及调节其下游基因血管内皮生长因子、促红细胞生成素等的表达，可能对糖尿病周围神经发挥保护作用。
Citation： 刘瑶丽,严宗逊. 缺氧诱导因子-1α与糖尿病周围神经病变. West China Medical Journal, 2012, 27(11): 1737-1740. doi: Copy
| 1. | Yang W, Lu J ,Weng J, et al. Prevalence of Diabetes among Men and Women in China[J]. N Engl J Med, 2010, 362(12): 1090-1101. |
| 2. | L lewelyn JG. The diabetic neuropathies: types, diagnosis and management[J]. J Neurol Neurosurg Psychiatry, 2003, 74(2): 5-7. |
| 3. | Yamada N, Horikawa Y, Oda N, et al. Genetic variation in the hypoxia-inducible factor-1αgene is associated with type 2 diabetes in Japanese[J]. J Clin Endocrinol Metab, 2005, 90(10): 5841-5847. |
| 4. | Hughes JM, Groot AJ, Groep P, et al. Active HIF-1 in the normal human retina[J]. J Histochem Cytochem, 2010, 58(3): 247-254. |
| 5. | Wang JJ, Zhang SX, Mott R, et al. Anti-inflammatory effects of pigment epithelium-derived factor in diabetic nephropathy[J]. Am J Physiol Renal Physiol, 2008, 294(5): 1166-1173. |
| 6. | 郑全林，徐向进. 缺氧诱导因子-1α与糖尿病慢性血管并发症[J]. 实用医学杂志， 2009, 25(4): 671-672. |
| 7. | Chavez JC, Almhanna K, Berti-Mattera LN. Transient expression of hypoxia-inducible factor-1 alpha and target genes in peripheral nerves from diabetic rats[J]. Neurosci Lett, 2005, 374(3): 179-182. |
| 8. | Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation[J]. Mol Cell Biol, 1992, 12(12): 5447-5454. |
| 9. | Bento CF, Pereira P. Regulation of hypoxia-inducible factor 1 and the loss of the cellular response to hypoxia in diabetes[J]. Diabetologia, 2011, 54(8): 1946-1956. |
| 10. | Botusan IR, Sunkari VG, Savu O, et al. Stabilization of HIF-1α is critical to improve wound healing in diabetic mice[J]. Proc Natl Acad Sci, 2009, 105(49): 19426-19431. |
| 11. | Molitoris KH, Kazi AA, Koos RD. Inhibition of oxygen-induced hypoxia-inducible factor-1 degradation unmasks estradiol induction of vascular endothelial growth factor expression in ecc-1 cancer cells in vitro[J]. Endocrinology, 2009, 150(12): 5405-5414. |
| 12. | Sarkar K, Talbot KF, Steenbergen C, et al. Adenoviral transfer of HIF-1 enhances vascular responses to critical limb ischemia in diabetic mice[J]. Proc Natl Acad Sci, 2009, 106(44): 18769-18774. |
| 13. | Forsythe JA, Jiang BH, Iyer NV, et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1[J]. Mol Cell Biol, 1996, 16(9): 4604-4613. |
| 14. | Semenza GL. HIF-1: Using two hands to flip the angiogenic switch[J]. Cancer Metastasis Rev, 2000, 19(1): 59-65. |
| 15. | Guillemin K, Krasnow MA. The hypoxic response: huffing and hifing[J]. Cell, 1997, 89(1): 9-12. |
| 16. | Catrina SB, Okamoto K, Pereira T, et al. Hyperglycemia regulates hypoxia-inducible factor-1α protein stability and function[J]. Diabetes, 2004, 53(12): 3226–3232. |
| 17. | Thangarajah H, Yao D, Chang EI, et al. The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues[J]. Proc Natl Acad Sci, 2009, 106(32): 13505-13510. |
| 18. | Marfella R, Amico MD, Filippo D, et al. Myocardial infarction in diabetic rats: role of hyperglycaemia on infarct size and early expression of hypoxia-inducible factor 1[J]. Diabetologia, 2002, 45(8): 1172–1181. |
| 19. | Obrosova IG, Fathallah L, Stevens MJ. Taurine counteracts oxidative stress and nerve growth factor deficit in early experimental diabetic neuropathy[J]. Exp Neurol, 2001, 172(1): 211-219. |
| 20. | Ran R, Xu H, Lu A, et al. Hypoxia preconditioning in the brain[J]. Dev Neurosci, 2005, 27(2): 87-92. |
| 21. | Xie L, Johnson RS, Freeman RS. Inhibition of NGF deprivation–induced death by low oxygen involves suppression of BIMEL and activation of HIF-1[J]. J Cell Biology, 2005, 168(6): 911-920. |
| 22. | 宋虎平，惠延年，王丽丽，等，缺氧诱导因子-1a在早期糖尿病大鼠视网膜神经细胞中的表达[J]. 眼科新进展，2006, 26(5): 331-335. |
| 23. | Schratzberger P, Walter DH, Rittig K, et al. Reversal of experimental diabetic neuropathy by VEGF gene transfer[J]. J Clin Invest, 2001, 107(9): 1083-1092. |
| 24. | Probst-Cousin S, Neundorfer B, Heuss D. Microvasculopathic neuromuscular diseases: Lessons from hypoxia-inducible factors[J]. Neuromuscul Disord, 2010, 20(3): 192-197. |
| 25. | Marfella R, Esposito K, Nappo F, et al. Expression of angiogenic factors during acute coronary syndromes in human type 2 diabetes[J]. Diabetes, 2004, 53(9): 2383-2391. |
| 26. | Huang YF, Yang CH, Huang CC, et al. Pharmacological and genetic accumulation of hypoxia-inducible factor-1α enhances excitatory synaptic transmission in hippocampal neurons through the production of vascular endothelial growth Factor[J]. J Neurosci, 2010, 30(17): 6080-6093. |
| 27. | Pichiule P, Chavez JC, Schmidt AM, et al. Hypoxia-inducible factor-1 mediates neuronal expression of the receptor for advanced glycation end products following hypoxia/ischemia[J]. Biol Chem, 2007, 282(50): 36330-36340. |
| 28. | Tacchini L, Ponti CD, Matteucci E, et al. Hepatocyte growth factor-activated NF-kB regulates HIF-1 activity and ODC expression, implicated in survival, differently in different carcinoma cell lines[J]. Carcinogenesis, 2004, 25(11): 2089-2100. |
| 29. | Dewhirst MW. Intermittent hypoxia furthers the rationale for hypoxia-inducible factor-1 targeting[J]. Cancer Res, 2007, 67(3): 854–855. |
| 30. | Piret JP, Minet E, Cosse JP, et al. Hypoxia-inducible factor-1-dependent overexpression of myeloid cell factor-1 protects hypoxic cells against tert-butyl hydroperoxide-induced apoptosis[J]. J Biol Chem, 2005, 280(10): 9336-9344. |
| 31. | Murakami T, Arai M, Sunada Y, et al. VEGF164 gene transfer by electroporation improves diabetic sensory neuropathy in mice[J]. J Gene Med, 2006, 8(6): 773–781. |
| 32. | Cheng L, Jia H, Lohr M, et al. Anti-chemorepulsive effects of vascular endothelial growth factor and placental growth factor-2 in dorsal root ganglion neurons are mediated via neuropilin-1 and cyclooxygenase-derived prostanoid production[J]. J Biol Chem, 2004, 279(29): 30654–30661. |
| 33. | Semenza GL. Regulation of oxygen homeostasis by hypoxia-inducible factor 1[J]. Physiology, 2009, 24(4): 97-106. |
| 34. | Campana WM, Myers RR. Erythropoietin and erythropoietin receptors in the peripheral nervous system: changes after nerve injury[J]. FASEB J, 2001, 15(10): 1804-1806. |
| 35. | Kilic E, Kilic U, Soliz J, et al. Brain-derived erythropoietin protects from focal cerebral ischemia by dual activation of ERK-1/-2 and Akt pathways[J]. FASEB J, 2005, 19(14): 2026-2028. |
| 36. | Yin ZS, Zhang H, Gao W. Erythropoietin promotes functional recovery and enhances nerve regeneration after peripheral nerve injury in rats[J]. AJNR Am J Neuroradiol, 2010, 31(3): 509-515. |
| 37. | Bianchi R, Buyukakilli B, Brines M, et al. Erythropoietin both protects from and reverses experimental diabetic neuropathy[J]. Proc Natl Acad Sci, 2004, 101(3): 823-828. |
| 38. | Chattopadhyay M, Walter C, Mata M, et al. Neuroprotective effect of herpes simplex virus-mediated gene transfer of erythropoietin in hyperglycemic dorsal root ganglion neurons[J]. Brain, 2009, 132(4): 879-888. |
| 39. | Taoufik E, Petit E, Divoux D, et al. TNF receptor I sensitizes neurons to erythropoietin and VEGF-mediated neuroprotection after ischemic and excitotoxic injury[J]. Proc Natl Acad Sci, 2008, 105(16): 6185-6190. |
| 40. | Weishaupt JH, Rohde G, Polking E, et al. Effect of erythropoietin axotomy-induced apoptosis in rat retinal ganglion cells[J]. Invest Ophthalmol Vis Sci, 2004, 45(5): 1514-1522. |
| 41. | Siren AL, Fratelli M, Brines M, et al. Erythropoietin prevents neuronal apoptosis aftercerebral ischemia and metabolic stress[J]. Proc Natl Acad Sci, 2001, 98(7): 4044-4049. |
| 42. | Shen JF, Wu YL, Xu JY, et al. ERK- and Akt-dependent neuroprotection by erythropoietin (EPO) against glyoxal-ages via modulation of bcl-xl, bax, and BAD[J]. Invest Ophthalmol Vis Sci, 2010, 51(1): 35-46. |
| 43. | Heinicke K, Baum O, Ogunshola O, et al. Excessive erythrocytosis in adult mice overexpressing erythropoietin leads to hepatic, renal, neuronal, and muscular degeneration[J]. Am J Physiol Regul Integr Comp Physiol, 2006, 291(4): 947-956. |
- 1. Yang W, Lu J ,Weng J, et al. Prevalence of Diabetes among Men and Women in China[J]. N Engl J Med, 2010, 362(12): 1090-1101.
- 2. L lewelyn JG. The diabetic neuropathies: types, diagnosis and management[J]. J Neurol Neurosurg Psychiatry, 2003, 74(2): 5-7.
- 3. Yamada N, Horikawa Y, Oda N, et al. Genetic variation in the hypoxia-inducible factor-1αgene is associated with type 2 diabetes in Japanese[J]. J Clin Endocrinol Metab, 2005, 90(10): 5841-5847.
- 4. Hughes JM, Groot AJ, Groep P, et al. Active HIF-1 in the normal human retina[J]. J Histochem Cytochem, 2010, 58(3): 247-254.
- 5. Wang JJ, Zhang SX, Mott R, et al. Anti-inflammatory effects of pigment epithelium-derived factor in diabetic nephropathy[J]. Am J Physiol Renal Physiol, 2008, 294(5): 1166-1173.
- 6. 郑全林，徐向进. 缺氧诱导因子-1α与糖尿病慢性血管并发症[J]. 实用医学杂志， 2009, 25(4): 671-672.
- 7. Chavez JC, Almhanna K, Berti-Mattera LN. Transient expression of hypoxia-inducible factor-1 alpha and target genes in peripheral nerves from diabetic rats[J]. Neurosci Lett, 2005, 374(3): 179-182.
- 8. Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation[J]. Mol Cell Biol, 1992, 12(12): 5447-5454.
- 9. Bento CF, Pereira P. Regulation of hypoxia-inducible factor 1 and the loss of the cellular response to hypoxia in diabetes[J]. Diabetologia, 2011, 54(8): 1946-1956.
- 10. Botusan IR, Sunkari VG, Savu O, et al. Stabilization of HIF-1α is critical to improve wound healing in diabetic mice[J]. Proc Natl Acad Sci, 2009, 105(49): 19426-19431.
- 11. Molitoris KH, Kazi AA, Koos RD. Inhibition of oxygen-induced hypoxia-inducible factor-1 degradation unmasks estradiol induction of vascular endothelial growth factor expression in ecc-1 cancer cells in vitro[J]. Endocrinology, 2009, 150(12): 5405-5414.
- 12. Sarkar K, Talbot KF, Steenbergen C, et al. Adenoviral transfer of HIF-1 enhances vascular responses to critical limb ischemia in diabetic mice[J]. Proc Natl Acad Sci, 2009, 106(44): 18769-18774.
- 13. Forsythe JA, Jiang BH, Iyer NV, et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1[J]. Mol Cell Biol, 1996, 16(9): 4604-4613.
- 14. Semenza GL. HIF-1: Using two hands to flip the angiogenic switch[J]. Cancer Metastasis Rev, 2000, 19(1): 59-65.
- 15. Guillemin K, Krasnow MA. The hypoxic response: huffing and hifing[J]. Cell, 1997, 89(1): 9-12.
- 16. Catrina SB, Okamoto K, Pereira T, et al. Hyperglycemia regulates hypoxia-inducible factor-1α protein stability and function[J]. Diabetes, 2004, 53(12): 3226–3232.
- 17. Thangarajah H, Yao D, Chang EI, et al. The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues[J]. Proc Natl Acad Sci, 2009, 106(32): 13505-13510.
- 18. Marfella R, Amico MD, Filippo D, et al. Myocardial infarction in diabetic rats: role of hyperglycaemia on infarct size and early expression of hypoxia-inducible factor 1[J]. Diabetologia, 2002, 45(8): 1172–1181.
- 19. Obrosova IG, Fathallah L, Stevens MJ. Taurine counteracts oxidative stress and nerve growth factor deficit in early experimental diabetic neuropathy[J]. Exp Neurol, 2001, 172(1): 211-219.
- 20. Ran R, Xu H, Lu A, et al. Hypoxia preconditioning in the brain[J]. Dev Neurosci, 2005, 27(2): 87-92.
- 21. Xie L, Johnson RS, Freeman RS. Inhibition of NGF deprivation–induced death by low oxygen involves suppression of BIMEL and activation of HIF-1[J]. J Cell Biology, 2005, 168(6): 911-920.
- 22. 宋虎平，惠延年，王丽丽，等，缺氧诱导因子-1a在早期糖尿病大鼠视网膜神经细胞中的表达[J]. 眼科新进展，2006, 26(5): 331-335.
- 23. Schratzberger P, Walter DH, Rittig K, et al. Reversal of experimental diabetic neuropathy by VEGF gene transfer[J]. J Clin Invest, 2001, 107(9): 1083-1092.
- 24. Probst-Cousin S, Neundorfer B, Heuss D. Microvasculopathic neuromuscular diseases: Lessons from hypoxia-inducible factors[J]. Neuromuscul Disord, 2010, 20(3): 192-197.
- 25. Marfella R, Esposito K, Nappo F, et al. Expression of angiogenic factors during acute coronary syndromes in human type 2 diabetes[J]. Diabetes, 2004, 53(9): 2383-2391.
- 26. Huang YF, Yang CH, Huang CC, et al. Pharmacological and genetic accumulation of hypoxia-inducible factor-1α enhances excitatory synaptic transmission in hippocampal neurons through the production of vascular endothelial growth Factor[J]. J Neurosci, 2010, 30(17): 6080-6093.
- 27. Pichiule P, Chavez JC, Schmidt AM, et al. Hypoxia-inducible factor-1 mediates neuronal expression of the receptor for advanced glycation end products following hypoxia/ischemia[J]. Biol Chem, 2007, 282(50): 36330-36340.
- 28. Tacchini L, Ponti CD, Matteucci E, et al. Hepatocyte growth factor-activated NF-kB regulates HIF-1 activity and ODC expression, implicated in survival, differently in different carcinoma cell lines[J]. Carcinogenesis, 2004, 25(11): 2089-2100.
- 29. Dewhirst MW. Intermittent hypoxia furthers the rationale for hypoxia-inducible factor-1 targeting[J]. Cancer Res, 2007, 67(3): 854–855.
- 30. Piret JP, Minet E, Cosse JP, et al. Hypoxia-inducible factor-1-dependent overexpression of myeloid cell factor-1 protects hypoxic cells against tert-butyl hydroperoxide-induced apoptosis[J]. J Biol Chem, 2005, 280(10): 9336-9344.
- 31. Murakami T, Arai M, Sunada Y, et al. VEGF164 gene transfer by electroporation improves diabetic sensory neuropathy in mice[J]. J Gene Med, 2006, 8(6): 773–781.
- 32. Cheng L, Jia H, Lohr M, et al. Anti-chemorepulsive effects of vascular endothelial growth factor and placental growth factor-2 in dorsal root ganglion neurons are mediated via neuropilin-1 and cyclooxygenase-derived prostanoid production[J]. J Biol Chem, 2004, 279(29): 30654–30661.
- 33. Semenza GL. Regulation of oxygen homeostasis by hypoxia-inducible factor 1[J]. Physiology, 2009, 24(4): 97-106.
- 34. Campana WM, Myers RR. Erythropoietin and erythropoietin receptors in the peripheral nervous system: changes after nerve injury[J]. FASEB J, 2001, 15(10): 1804-1806.
- 35. Kilic E, Kilic U, Soliz J, et al. Brain-derived erythropoietin protects from focal cerebral ischemia by dual activation of ERK-1/-2 and Akt pathways[J]. FASEB J, 2005, 19(14): 2026-2028.
- 36. Yin ZS, Zhang H, Gao W. Erythropoietin promotes functional recovery and enhances nerve regeneration after peripheral nerve injury in rats[J]. AJNR Am J Neuroradiol, 2010, 31(3): 509-515.
- 37. Bianchi R, Buyukakilli B, Brines M, et al. Erythropoietin both protects from and reverses experimental diabetic neuropathy[J]. Proc Natl Acad Sci, 2004, 101(3): 823-828.
- 38. Chattopadhyay M, Walter C, Mata M, et al. Neuroprotective effect of herpes simplex virus-mediated gene transfer of erythropoietin in hyperglycemic dorsal root ganglion neurons[J]. Brain, 2009, 132(4): 879-888.
- 39. Taoufik E, Petit E, Divoux D, et al. TNF receptor I sensitizes neurons to erythropoietin and VEGF-mediated neuroprotection after ischemic and excitotoxic injury[J]. Proc Natl Acad Sci, 2008, 105(16): 6185-6190.
- 40. Weishaupt JH, Rohde G, Polking E, et al. Effect of erythropoietin axotomy-induced apoptosis in rat retinal ganglion cells[J]. Invest Ophthalmol Vis Sci, 2004, 45(5): 1514-1522.
- 41. Siren AL, Fratelli M, Brines M, et al. Erythropoietin prevents neuronal apoptosis aftercerebral ischemia and metabolic stress[J]. Proc Natl Acad Sci, 2001, 98(7): 4044-4049.
- 42. Shen JF, Wu YL, Xu JY, et al. ERK- and Akt-dependent neuroprotection by erythropoietin (EPO) against glyoxal-ages via modulation of bcl-xl, bax, and BAD[J]. Invest Ophthalmol Vis Sci, 2010, 51(1): 35-46.
- 43. Heinicke K, Baum O, Ogunshola O, et al. Excessive erythrocytosis in adult mice overexpressing erythropoietin leads to hepatic, renal, neuronal, and muscular degeneration[J]. Am J Physiol Regul Integr Comp Physiol, 2006, 291(4): 947-956.