The pathophysiology of retinal ischemia involves mechanisms including inflammation and apoptosis. Ischemic post-conditioning (Post-C), a brief non-lethal ischemia, induces a long-term ischemic tolerance, but the mechanisms of ischemic post-conditioning in the retina have only been described on a limited basis. Accordingly, we conducted this study to determine the molecular events in retinal ischemic post-conditioning and to identify targets for therapeutic strategies for retinal ischemia.
To determine global molecular events in ischemic post-conditioning, a comprehensive study of the transcriptome of whole retina was performed. We utilized RNA sequencing (RNA-Seq), a recently developed, deep sequencing technique enabling quantitative gene expression, with low background noise, dynamic detection range, and discovery of novel genes. Rat retina was subjected to ischemia in vivo by elevation of intraocular pressure above systolic blood pressure. At 24 h after ischemia, Post-C or sham Post-C was performed by another, briefer period of ischemia, and 24 h later, retinas were collected and RNA processed.
There were 71 significantly affected pathways in post-conditioned/ischemic vs. normals and 43 in sham post conditioned/ischemic vs. normals. Of these, 28 were unique to Post-C and ischemia. Seven biological pathways relevant to ischemic injury, in Post-C as opposed to sham Post-C, were examined in detail. Apoptosis, p53, cell cycle, JAK-STAT, HIF-1, MAPK and PI3K-Akt pathways significantly differed in the number as well as degree of fold change in genes between conditions.
Post-C is a complex molecular signaling process with a multitude of altered molecular pathways. We identified potential gene candidates in Post-C. Studying the impact of altering expression of these factors may yield insight into new methods for treating or preventing damage from retinal ischemic disorders.
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This study was supported by the National Institutes of Health (Rockville, MD, USA) grant EY10343 to Dr. Roth, UL1TR000050 to the Center for Clinical and Translational Sciences of the University of Illinois at Chicago, the Illinois Society for the Prevention of Blindness, Chicago, IL, USA (Ms. Stelman); the Craig Foundation (Chicago, IL, USA, Ms. Stelman), a medical student research fellowship grant from the Foundation for Anesthesia Education and Research (Schaumburg, IL, USA, Ms. Stelman), and Core Grant P30 EY001792 (to the Department of Ophthalmology, University of Illinois at Chicago from the National Institutes of Health, Rockville, MD, USA); There was no involvement of the funding bodies in the design of the study or in collection, analysis and interpretation of the data or the writing of the manuscript. None of the authors have any conflicts of interest.
Ethical approval: All procedures performed in studies involving animals were in accordance with the ethical standards of and approved by the Institutional Animal Care and Use Committee of the University of Illinois at Chicago.
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Kadzielawa, K., Mathew, B., Stelman, C.R. et al. Gene expression in retinal ischemic post-conditioning. Graefes Arch Clin Exp Ophthalmol 256, 935–949 (2018). https://doi.org/10.1007/s00417-018-3905-0