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ERK- and Akt-dependent neuroprotection by erythropoietin (EPO) against glyoxal-AGEs via modulation of Bcl-xL, Bax, and BAD.
Invest Ophthalmol Vis Sci. 2010 Jan; 51(1):35-46.IO

Abstract

PURPOSE

To characterize the neuroprotective mechanisms of erythropoietin (EPO) against the stress of glyoxal-advanced glycation end products (AGEs) in retinal neuronal cells.

METHODS

Rat retinal organ culture, primary retinal neuron culture, and retinal cell line (R28 cell) culture under glyoxal-AGEs insult were used as in vitro models. Exogenous EPO was applied to these models. Retinal neuronal cell death was assessed by TUNEL, ethidium bromide/acridine orange staining, and cell viability assay. R28 cell proliferation was evaluated by BrdU incorporation and propidium iodide staining. Real-time RT-PCR and Western blot analysis were used to detect Bcl-xL, Bcl-2, Bax, BAD, and products of extracellular signal regulated kinase (ERK) and Akt pathways. Specific inhibitors and plasmids were used to pinpoint the roles of ERK and Akt pathways. Results. EPO protected the retinal cells from glyoxal-AGE-induced injury in a time- and dose-dependent fashion. The protective function of EPO was proved to be antiapoptotic, not pro-cell proliferative. Glyoxal upregulated Bax expression but suppressed Bcl-xL expression and BAD phosphorylation. In contrast, EPO enhanced BAD phosphorylation and Bcl-xL expression but downregulated Bax. The regulation of these apoptosis-related proteins by EPO was through ERK and Akt pathways.

CONCLUSIONS

These data demonstrate that exogenous EPO significantly attenuates the retinal neuronal cell death induced by glyoxal-AGEs by promoting antiapoptotic and suppressing apoptotic proteins. EPO/EPO receptor signaling through ERK and Akt pathways is pivotal in EPO neuroprotective mechanisms.

Authors+Show Affiliations

Laboratory of Clinical Visual Sciences, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19628748

Citation

Shen, Jianfeng, et al. "ERK- and Akt-dependent Neuroprotection By Erythropoietin (EPO) Against glyoxal-AGEs Via Modulation of Bcl-xL, Bax, and BAD." Investigative Ophthalmology & Visual Science, vol. 51, no. 1, 2010, pp. 35-46.
Shen J, Wu Y, Xu JY, et al. ERK- and Akt-dependent neuroprotection by erythropoietin (EPO) against glyoxal-AGEs via modulation of Bcl-xL, Bax, and BAD. Invest Ophthalmol Vis Sci. 2010;51(1):35-46.
Shen, J., Wu, Y., Xu, J. Y., Zhang, J., Sinclair, S. H., Yanoff, M., Xu, G., Li, W., & Xu, G. T. (2010). ERK- and Akt-dependent neuroprotection by erythropoietin (EPO) against glyoxal-AGEs via modulation of Bcl-xL, Bax, and BAD. Investigative Ophthalmology & Visual Science, 51(1), 35-46. https://doi.org/10.1167/iovs.09-3544
Shen J, et al. ERK- and Akt-dependent Neuroprotection By Erythropoietin (EPO) Against glyoxal-AGEs Via Modulation of Bcl-xL, Bax, and BAD. Invest Ophthalmol Vis Sci. 2010;51(1):35-46. PubMed PMID: 19628748.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - ERK- and Akt-dependent neuroprotection by erythropoietin (EPO) against glyoxal-AGEs via modulation of Bcl-xL, Bax, and BAD. AU - Shen,Jianfeng, AU - Wu,Yalan, AU - Xu,Jing-Ying, AU - Zhang,Jingfa, AU - Sinclair,Stephen H, AU - Yanoff,Myron, AU - Xu,Guoxu, AU - Li,Weiye, AU - Xu,Guo-Tong, Y1 - 2009/07/23/ PY - 2009/7/25/entrez PY - 2009/7/25/pubmed PY - 2010/2/4/medline SP - 35 EP - 46 JF - Investigative ophthalmology & visual science JO - Invest Ophthalmol Vis Sci VL - 51 IS - 1 N2 - PURPOSE: To characterize the neuroprotective mechanisms of erythropoietin (EPO) against the stress of glyoxal-advanced glycation end products (AGEs) in retinal neuronal cells. METHODS: Rat retinal organ culture, primary retinal neuron culture, and retinal cell line (R28 cell) culture under glyoxal-AGEs insult were used as in vitro models. Exogenous EPO was applied to these models. Retinal neuronal cell death was assessed by TUNEL, ethidium bromide/acridine orange staining, and cell viability assay. R28 cell proliferation was evaluated by BrdU incorporation and propidium iodide staining. Real-time RT-PCR and Western blot analysis were used to detect Bcl-xL, Bcl-2, Bax, BAD, and products of extracellular signal regulated kinase (ERK) and Akt pathways. Specific inhibitors and plasmids were used to pinpoint the roles of ERK and Akt pathways. Results. EPO protected the retinal cells from glyoxal-AGE-induced injury in a time- and dose-dependent fashion. The protective function of EPO was proved to be antiapoptotic, not pro-cell proliferative. Glyoxal upregulated Bax expression but suppressed Bcl-xL expression and BAD phosphorylation. In contrast, EPO enhanced BAD phosphorylation and Bcl-xL expression but downregulated Bax. The regulation of these apoptosis-related proteins by EPO was through ERK and Akt pathways. CONCLUSIONS: These data demonstrate that exogenous EPO significantly attenuates the retinal neuronal cell death induced by glyoxal-AGEs by promoting antiapoptotic and suppressing apoptotic proteins. EPO/EPO receptor signaling through ERK and Akt pathways is pivotal in EPO neuroprotective mechanisms. SN - 1552-5783 UR - https://www.unboundmedicine.com/medline/citation/19628748/ERK__and_Akt_dependent_neuroprotection_by_erythropoietin__EPO__against_glyoxal_AGEs_via_modulation_of_Bcl_xL_Bax_and_BAD_ L2 - https://iovs.arvojournals.org/article.aspx?doi=10.1167/iovs.09-3544 DB - PRIME DP - Unbound Medicine ER -