Skip to main content Accessibility help
×
Home

Protective effects of remote ischemic conditioning against ischemia/reperfusion-induced retinal injury in rats

  • XUXIANG ZHANG (a1), YUNNENG JIZHANG (a2) (a3), XIAOYING XU (a1), TIMOTHY D. KWIECIEN (a4), NING LI (a3), YING ZHANG (a3), XUNMING JI (a5), CHANGHONG REN (a1) (a3) and YUCHUAN DING (a4)...

Abstract

Limb remote ischemic conditioning (LRIC) provides a physiologic strategy for harnessing the body’s endogenous protective capabilities against injury induced by ischemia–reperfusion in the central nervous system. The aim of the present study was to determine if LRIC played a role in protecting the retina from ischemia–reperfusion injury. A total of 81 adult male Sprague-Dawley rats were randomly assigned to sham and ischemia/reperfusion with or without remote LRIC arms. The retinal ischemic model was generated through right middle cerebral artery occlusion (MCAO) and pterygopalatine artery occlusion for 60 min followed by 1, 3, and 7 days of subsequent reperfusion. LRIC was conducted immediately following MCAO by tightening a tourniquet around the upper thigh and releasing for three cycles. Paraffin sections were stained with hematoxylin and eosin in order to quantify the number of cells in retinal ganglion cells (RGCs) layer throughout the duration of the study. Cellular expression of glial fibrillary acidic protein (GFAP) was detected and examined through immunohistochemistry. Protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) was also analyzed by Western blot techniques. Our study demonstrated that the loss of cells in RGC layer was attenuated by LRIC treatment at 3 and 7 days following reperfusion (P < 0.05). Immunohistochemistry studies depicted a gradual increase (P < 0.05) in GFAP levels from day 1 through day 7 following ischemia and subsequent reperfusion, whereas LRIC reduced GFAP levels at 1, 3, and 7 days postreperfusion. In addition, LRIC increased the expression of Nrf2 and HO-1 at day 1 and 3 following ischemia/reperfusion. This particular study is the first remote conditioning study applicable to retinal ischemia. Our results strongly support the position that LRIC may be used as a noninvasive neuroprotective strategy, which provides retinal protection from ischemia–reperfusion injury through the upregulation of antioxidative stress proteins, such as Nrf2 and HO-1.

Copyright

Corresponding author

Address correspondence to: Changhong Ren, Institute of Hypoxia Medicine, Xuanwu Hospital, Capital Medical University, Beijing 100053, China. E-mail: ren97hong2001@aliyun.com

References

Hide All
Arai-Gaun, S., Katai, N., Kikuchi, T., Kurokawa, T., Ohta, K. & Yoshimura, N. (2004). Heme oxygenase-1 induced in muller cells plays a protective role in retinal ischemia-reperfusion injury in rats. Investigative Ophthalmology & Visual Science 45, 42264232.
Block, F., Grommes, C., Kosinski, C., Schmidt, W. & Schwarz, M. (1997). Retinal ischemia induced by the intraluminal suture method in rats. Neuroscience Letters 232, 4548.
Botker, H.E., Kharbanda, R., Schmidt, M.R., Bottcher, M., Kaltoft, A.K., Terkelsen, C.J., Munk, K., Andersen, N.H., Hansen, T.M., Trautner, S., Lassen, J.F., Christiansen, E.H., Krusell, L.R., Kristensen, S.D., Thuesen, L., Nielsen, S.S., Rehling, M., Sorensen, H.T., Redington, A.N. & Nielsen, T.T. (2010). Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet 375, 727734.
Dreixler, J.C., Bratton, A., Du, E., Shaikh, A.R., Savoie, B., Alexander, M., Marcet, M.M & Roth, S. (2011 a). Mitogen-activated protein kinase phosphatase-1 (MKP-1) in retinal ischemic preconditioning. Experimental Eye Research 93, 340349.
Dreixler, J.C., Sampat, A., Shaikh, A.R., Alexander, M., Marcet, M.M & Roth, S. (2011 b). Protein kinase B (Akt) and mitogen-activated protein kinase p38alpha in retinal ischemic post-conditioning. Journal of Molecular Neuroscience 45, 309320.
Eng, L.F., Ghirnikar, R.S. & Lee, Y.L. (2000). Glial fibrillary acidic protein: GFAP-thirty-one years (1969-2000). Neurochemical Research 25, 14391451.
Fernandez, D.C., Bordone, M.P., Chianelli, M.S. & Rosenstein, R.E. (2009 a). Retinal neuroprotection against ischemia-reperfusion damage induced by postconditioning. Investigative Ophthalmology & Visual Science 50, 39223930.
Fernandez, D.C., Chianelli, M.S. & Rosenstein, R.E. (2009 b). Involvement of glutamate in retinal protection against ischemia/reperfusion damage induced by post-conditioning. Journal of Neurochemistry 111, 488498.
Flammer, J., Orgul, S., Costa, V.P., Orzalesi, N., Krieglstein, G.K., Serra, L.M., Renard, J.P. & Stefansson, E. (2002). The impact of ocular blood flow in glaucoma. Progress in Retinal and Eye Research 21, 359393.
Hausenloy, D.J. & Yellon, D.M. (2008). Remote ischaemic preconditioning: Underlying mechanisms and clinical application. Cardiovascular Research 79, 377386.
Hausenloy, D.J. & Yellon, D.M. (2011). The therapeutic potential of ischemic conditioning: An update. Nature Reviews Cardiology 8, 619629.
He, M., Pan, H., Chang, R.C., So, K.F., Brecha, N.C. & Pu, M. (2014). Activation of the Nrf2/HO-1 antioxidant pathway contributes to the protective effects of Lycium barbarum polysaccharides in the rodent retina after ischemia-reperfusion-induced damage. PLoS One 9, e84800.
Hoda, M.N., Siddiqui, S., Herberg, S., Periyasamy-Thandavan, S., Bhatia, K., Hafez, S.S., Johnson, M.H., Hill, W.D., Ergul, A., Fagan, S.C. & Hess, D.C. (2012). Remote ischemic perconditioning is effective alone and in combination with intravenous tissue-type plasminogen activator in murine model of embolic stroke. Stroke 43, 27942799.
Jadhav, A.P., Roesch, K. & Cepko, C.L. (2009). Development and neurogenic potential of Muller glial cells in the vertebrate retina. Progress in Retinal and Eye Research 28, 249262.
Lai, I.R., Chang, K.J., Chen, C.F. & Tsai, H.W. (2006). Transient limb ischemia induces remote preconditioning in liver among rats: The protective role of heme oxygenase-1. Transplantation 81, 13111317.
Lee, J.M., Calkins, M.J., Chan, K., Kan, Y.W. & Johnson, J.A. (2003). Identification of the NF-E2-related factor-2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis. The Journal of Biological Chemistry 278, 1202912038.
Li, S.Y., Fu, Z.J. & Lo, A.C. (2012). Hypoxia-induced oxidative stress in ischemic retinopathy. Oxidative Medicine and Cellular Longevity 2012, 426769.
Meng, R., Asmaro, K., Meng, L., Liu, Y., Ma, C., Xi, C., Li, G., Ren, C., Luo, Y., Ling, F., Jia, J., Hua, Y., Wang, X., Ding, Y., Lo, E.H. & Ji, X. (2012). Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. Neurology 79, 18531861.
Moi, P., Chan, K., Asunis, I., Cao, A. & Kan, Y.W. (1994). Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proceedings of the National Academy of Sciences of the United States of America 91, 99269930.
Obolensky, A., Berenshtein, E., Konijn, A.M., Banin, E. & Chevion, M. (2008). Ischemic preconditioning of the rat retina: Protective role of ferritin. Free Radical Biology & Medicine 44, 12861294.
Osborne, N.N., Block, F. & Sontag, K.H. (1991). Reduction of ocular blood flow results in glial fibrillary acidic protein (GFAP) expression in rat retinal Muller cells. Visual Neuroscience 7, 637639.
Osborne, N.N., Casson, R.J., Wood, J.P., Chidlow, G., Graham, M. & Melena, J. (2004). Retinal ischemia: Mechanisms of damage and potential therapeutic strategies. Progress in Retinal and Eye Research 23, 91147.
Owuor, E.D. & Kong, A.N. (2002). Antioxidants and oxidants regulated signal transduction pathways. Biochemical Pharmacology 64, 765770.
Ren, C., Gao, M., Dornbos, D. 3rd, Ding, Y., Zeng, X., Luo, Y. & Ji, X. (2012). Remote ischemic post-conditioning reduced brain damage in experimental ischemia/reperfusion injury. Neurological Research 33, 514519.
Satoh, T., Okamoto, S.I., Cui, J., Watanabe, Y., Furuta, K., Suzuki, M., Tohyama, K. & Lipton, S.A. (2006). Activation of the Keap1/Nrf2 pathway for neuroprotection by electrophilic [correction of electrophilic] phase II inducers. Proceedings of the National Academy of Sciences of the United States of America 103, 768773.
Saxena, P., Newman, M.A., Shehatha, J.S., Redington, A.N. & Konstantinov, I.E. (2010). Remote ischemic conditioning: Evolution of the concept, mechanisms, and clinical application. Journal of Cardiac Surgery 25, 127134.
Shah, Z.A., Li, R., Thimmulappa, R.K., Kensler, T.W., Yamamoto, M., Biswal, S. & Dore, S. (2007). Role of reactive oxygen species in modulation of Nrf2 following ischemic reperfusion injury. Neuroscience 147, 5359.
Shelton, P. & Jaiswal, A.K. (2013). The transcription factor NF-E2-related factor 2 (Nrf2): A protooncogene? FASEB Journal 27, 414423.
Shokeir, A.A., Hussein, A.M., Barakat, N., Abdelaziz, A., Elgarba, M. & Awadalla, A. (2014). Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf-2-dependent genes by ischaemic pre-conditioning and post-conditioning: New adaptive endogenous protective responses against renal ischaemia/reperfusion injury. Acta Physiologica (Oxford). 210, 342353.
Veighey, K. & Macallister, R.J. (2012). Clinical applications of remote ischemic preconditioning. Cardiology Research and Practice 2012, 620681.
Verma, D. (1993). Pathogenesis of diabetic retinopathy – The missing link? Medical Hypotheses 41, 205210.
Wei, M., Xin, P., Li, S., Tao, J., Li, Y., Li, J., Liu, M., Zhu, W. & Redington, A.N. (2011). Repeated remote ischemic postconditioning protects against adverse left ventricular remodeling and improves survival in a rat model of myocardial infarction. Circulation Research 108, 12201225.
Zhang, C., Rosenbaum, D.M., Shaikh, A.R., Li, Q., Rosenbaum, P.S., Pelham, D.J. & Roth, S. (2002). Ischemic preconditioning attenuates apoptotic cell death in the rat retina. Investigative Ophthalmology & Visual Science 43, 30593066.
Zhao, H. (2009). Ischemic postconditioning as a novel avenue to protect against brain injury after stroke. Journal of Cerebral Blood Flow and Metabolism 29, 873885.
Zhao, J., Kobori, N., Aronowski, J. & Dash, P.K. (2006). Sulforaphane reduces infarct volume following focal cerebral ischemia in rodents. Neuroscience Letters 393, 108112.
Zhao, Z.Q. & Vinten-Johansen, J. (2006). Postconditioning: Reduction of reperfusion-induced injury. Cardiovascular Research 70, 200211.
Zhu, Y., Zhang, Y., Ojwang, B.A., Brantley, M.A. Jr. & Gidday, J.M. (2007). Long-term tolerance to retinal ischemia by repetitive hypoxic preconditioning: Role of HIF-1alpha and heme oxygenase-1. Investigative Ophthalmology & Visual Science 48, 17351743.

Keywords

Related content

Powered by UNSILO

Protective effects of remote ischemic conditioning against ischemia/reperfusion-induced retinal injury in rats

  • XUXIANG ZHANG (a1), YUNNENG JIZHANG (a2) (a3), XIAOYING XU (a1), TIMOTHY D. KWIECIEN (a4), NING LI (a3), YING ZHANG (a3), XUNMING JI (a5), CHANGHONG REN (a1) (a3) and YUCHUAN DING (a4)...

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed.