BDNF protects retinal neurons from hyperglycemia through the TrkB/ERK/MAPK pathway

Liu,Yu; Tao,Lijian; Fu,Xiao; Zhao,Yingchun; Xu,Xueliang

doi:10.3892/mmr.2013.1433

BDNF protects retinal neurons from hyperglycemia through the TrkB/ERK/MAPK pathway

Authors:
- Yu Liu
- Lijian Tao
- Xiao Fu
- Yingchun Zhao
- Xueliang Xu
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Affiliations: Department of Ophthalmology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China, Department of Nephrology, Xiangya Hospital, Changsha, Hunan 410008, P.R. China, Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA, Department of Ophthalmology, Xiangya Hospital, Changsha, Hunan 410008, P.R. China
Published online on: April 18, 2013 https://doi.org/10.3892/mmr.2013.1433
Pages: 1773-1778

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Abstract

Diabetic retinopathy (DR) is one of the most common diabetic eye diseases and a leading cause of blindness. It is characterized by changes in the blood vessels of the retina. The pathogenesis of DR is complex and to date, the precise mechanisms involved remain unclear. Previous studies have reported that DR is associated with neurodegeneration and that apoptosis may occur in diabetic retinas. In the present study, retinal neurons under conditions of hyperglycemia were used as a model to study apoptosis in diabetic retinas. Retinal neurons exposed to hyperglycemia exhibited high levels of apoptosis. Brain‑derived neurotrophic factor (BDNF), a member of the neurotrophin family, was effective in protecting retinal neurons from hyperglycemia in vitro. BDNF promoted neuronal cell survival in a concentration‑dependent manner. In addition, BDNF was demonstrated to promote the expression of tropomyosin‑related kinase B (TrkB) and elevate the phosphorylation levels of TrkB and ERK in retinal neurons exposed to hyperglycemia. The results of the present study demonstrated that BDNF may protect retinal neurons from hyperglycemia via the TrkB/ERK/MAPK pathway and provides novel insights into the pathogenesis of DR.

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1	Barber AJ: A new view of diabetic retinopathy: a neurodegenerative disease of the eye. Prog Neuropsychopharmacol Biol Psychiatry. 27:283–290. 2003. View Article : Google Scholar : PubMed/NCBI
2	Lieth E, Barber AJ, Xu B, et al: Glial reactivity and impaired glutamate metabolism in short-term experimental diabetic retinopathy. Penn State Retina Research Group. Diabetes. 47:815–820. 1998. View Article : Google Scholar : PubMed/NCBI
3	Fernyhough P, Huang TJ and Verkhratsky A: Mechanism of mitochondrial dysfunction in diabetic sensory neuropathy. J Peripher Nerv Syst. 8:227–235. 2003. View Article : Google Scholar : PubMed/NCBI
4	Mey J and Thanos S: Intravitreal injections of neurotrophic factors support the survival of axotomized retinal ganglion cells in adult rats in vivo. Brain Res. 602:304–317. 1993. View Article : Google Scholar : PubMed/NCBI
5	Peinado-Ramón P, Salvador M, Villegas-Pérez MP and Vidal-Sanz M: Effects of axotomy and intraocular administration of NT-4, NT-3 and brain-derived neurotrophic factor on the survival of adult rat retinal ganglion cells. A quantitative in vivo study Invest Ophthalmol Vis Sci. 37:489–500. 1996.PubMed/NCBI
6	Pinzón-Duarte G, Arango-González B, Guenther E and Kohler K: Effects of brain-derived neurotrophic factor on cell survival, differentiation and patterning of neuronal connections and Müller glia cells in the developing retina. Eur J Neurosci. 19:1475–1484. 2004.PubMed/NCBI
7	Seigel GM, Chiu L and Paxhia A: Inhibition of neuroretinal cell death by insulin-like growth factor-1 and its analogs. Mol Vis. 6:157–163. 2000.PubMed/NCBI
8	Müller A, Hauk TG and Fischer D: Astrocyte-derived CNTF switches mature RGCs to a regenerative state following inflammatory stimulation. Brain. 130:3308–3320. 2007.PubMed/NCBI
9	Murphy JA, Franklin TB, Rafuse VF and Clarke DB: The neural cell adhesion molecule is necessary for normal adult retinal ganglion cell number and survival. Mol Cell Neurosci. 36:280–292. 2007. View Article : Google Scholar : PubMed/NCBI
10	Liu X, Clark AF and Wordinger RJ: Expression of ciliary neurotrophic factor (CNTF) and its tripartite receptor complex by cells of the human optic nerve head. Mol Vis. 13:758–763. 2007.PubMed/NCBI
11	Yoshii A and Constantine-Paton M: Postsynaptic BDNF-TrkB signaling in synapse maturation, plasticity and disease. Dev Neurobiol. 70:304–322. 2010.PubMed/NCBI
12	Hetman M, Kanning K, Cavanaugh JE and Xia Z: Neuroprotection by brain-derived neurotrophic factor is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase. J Biol Chem. 274:22569–22580. 1999. View Article : Google Scholar : PubMed/NCBI
13	Almeida RD, Manadas BJ, Melo CV, et al: Neuroprotection by BDNF against glutamate-induced apoptotic cell death is mediated by ERK and PI3-kinase pathways. Cell Death Differ. 12:1329–1343. 2005. View Article : Google Scholar : PubMed/NCBI
14	Bonni A, Brunet A, West AE, Datta SR, Takasu MA and Greenberg ME: Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science. 286:1358–1362. 1999. View Article : Google Scholar : PubMed/NCBI
15	Han BH and Holtzman DM: BDNF protects the neonatal brain from hypoxic-ischemic injury in vivo via the ERK pathway. J Neurosci. 20:5775–5781. 2000.PubMed/NCBI
16	Satoh T, Nakatsuka D, Watanabe Y, Nagata I, Kikuchi H and Namura S: Neuroprotection by MAPK/ERK kinase inhibition with U0126 against oxidative stress in a mouse neuronal cell line and rat primary cultured cortical neurons. Neurosci Lett. 288:163–166. 2000. View Article : Google Scholar
17	Jin K, Mao XO, Zhu Y and Greenberg DA: MEK and ERK protect hypoxic cortical neurons via phosphorylation of Bad. J Neurochem. 80:119–125. 2002. View Article : Google Scholar : PubMed/NCBI
18	Klöcker N, Kermer P, Weishaupt JH, Labes M, Ankerhold R and Bähr M: Brain-derived neurotrophic factor-mediated neuroprotection of adult rat retinal ganglion cells in vivo does not exclusively depend on phosphatidyl-inositol-3′-kinase/protein kinase B signaling. J Neurosci. 20:6962–6967. 2000.PubMed/NCBI
19	Meng M, Zhiling W, Hui Z, Shengfu L, Dan Y and Jiping H: Cellular levels of TrkB and MAPK in the neuroprotective role of BDNF for embryonic rat cortical neurons against hypoxia in vitro. Int J Dev Neurosci. 23:515–521. 2005. View Article : Google Scholar : PubMed/NCBI
20	Song XY, Li F, Zhang FH, Zhong JH and Zhou XF: Peripherally-derived BDNF promotes regeneration of ascending sensory neurons after spinal cord injury. PLoS One. 3:e17072008. View Article : Google Scholar : PubMed/NCBI
21	Fromowitz FB, Viola MV, Chao S, et al: ras p21 expression in the progression of breast cancer. Hum Pathol. 18:1268–1275. 1987. View Article : Google Scholar : PubMed/NCBI
22	Hicks RR, Martin VB, Zhang L and Seroogy KB: Mild experimental brain injury differentially alters the expression of neurotrophin and neurotrophin receptor mRNAs in the hippocampus. Exp Neurol. 160:469–478. 1999. View Article : Google Scholar : PubMed/NCBI
23	Cui Q, Tang LS, Hu B, So KF and Yip HK: Expression of trkA, trkB and trkC in injured and regenerating retinal ganglion cells of adult rats. Invest Ophthalmol Vis Sci. 43:1954–1964. 2002.PubMed/NCBI
24	Abu El-Asrar AM, Dralands L, Missotten L and Geboes K: Expression of antiapoptotic and proapoptotic molecules in diabetic retinas. Eye (Lond). 21:238–245. 2007.PubMed/NCBI
25	Santiago AR, Cristóvão AJ, Santos PF, Carvalho CM and Ambrósio AF: High glucose induces caspase-independent cell death in retinal neural cells. Neurobiol Dis. 25:464–472. 2007. View Article : Google Scholar : PubMed/NCBI
26	Li YH, Zhuo YH, Lü L, et al: Caspase-dependent retinal ganglion cell apoptosis in the rat model of acute diabetes. Chin Med J (Engl). 121:2566–2571. 2008.PubMed/NCBI
27	Oshitari T, Yamamoto S, Hata N and Roy S: Mitochondria- and caspase-dependent cell death pathway involved in neuronal degeneration in diabetic retinopathy. Br J Ophthalmol. 92:552–556. 2008. View Article : Google Scholar : PubMed/NCBI
28	Omori K, Naruishi K, Nishimura F, Yamada-Naruishi H and Takashiba S: High glucose enhances interleukin-6-induced vascular endothelial growth factor 165 expression via activation of gp130-mediated p44/42 MAPK-CCAAT/enhancer binding protein signaling in gingival fibroblasts. J Biol Chem. 279:6643–6649. 2004. View Article : Google Scholar