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Modulation of RAGE Isoforms Expression in the Brain and Plasma of Rats Exposed to Transient Focal Cerebral Ischemia

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Abstract

Activation of RAGE (receptor for advanced glycation endproducts) and of its subtypes may play a role in neuronal damage and neuroinflammation associated with brain ischemia, though the underlying mechanisms remain unclear. In this study, we have examined by Western blotting the expression of RAGE isoforms in the cerebral cortex and striatum of Wistar rats subjected to transient (1 or 2 h) middle cerebral artery occlusion (tMCAo). The findings show that the full-length RAGE (~50 kDa) and its isoforms in the 26–43 kDa range are significantly decreased in the ischemic cortex, but not in the striatum, after 1 and 2 h tMCAo when compared to the sham group. By contrast, in the striatum, ischemia—reperfusion injury caused a significant increase of full-length RAGE and its isoforms in the 72–100 kDa range. We also investigated the soluble form of RAGE, which was significantly decreased in the plasma of rats subjected to transient or permanent MCAo. In conclusion, the present data demonstrate that regional brain expression of RAGE is differentially affected by tMCAo in rat. These modifications are accompanied by a decrease in the plasma levels of soluble RAGE, thereby suggesting a potential role for soluble RAGE as a peripheral biomarker of focal ischemia.

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References

  1. Amantea D, Nappi G, Bernardi G, Bagetta G, Corasaniti MT (2009) Post-ischemic brain damage: pathophysiology and role of inflammatory mediators. FEBS J 276:13–26

    Article  PubMed  CAS  Google Scholar 

  2. Yamagishi S, Matsui T (2010) Soluble form of a receptor for advanced glycation end products (sRAGE) as a biomarker. Front Biosci (Elite Ed) 2:1184–1195

    Article  Google Scholar 

  3. Kislinger T, Fu C, Huber B, Qu W, Taguchi A, Du Yan S, Hofmann M, Yan SF, Pischetsrieder M, Stern D, Schmidt AM (1999) N(epsilon)-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression. Biol Chem 274:31740–31749

    Article  CAS  Google Scholar 

  4. Ramasamy R, Yan SF, Schmidt AM (2009) RAGE: therapeutic target and biomarker of the inflammatory response—the evidence mounts. J Leukoc Biol 86:505–512

    Article  PubMed  CAS  Google Scholar 

  5. Fang F, Lue LF, Yan S, Xu H, Luddy JS, Chen D, Walker DG, Stern DM, Yan S, Schmidt AM, Chen JX, Yan SS (2010) RAGE-dependent signaling in microglia contributes to neuroinflammation, Abeta accumulation, and impaired learning/memory in a mouse model of Alzheimer’s disease. FASEB J 24:1043–1055

    Article  PubMed  CAS  Google Scholar 

  6. Muhammad S, Barakat W, Stoyanov S, Murikinati S, Yang H, Tracey KJ, Bendszus M, Rossetti G, Nawroth PP, Bierhaus A, Schwaninger M (2008) The HMGB1 receptor RAGE mediates ischemic brain damage. J Neurosci 28:12023–12031

    Article  PubMed  CAS  Google Scholar 

  7. Ma L, Carter RJ, Morton AJ, Nicholson LF (2003) RAGE is expressed in pyramidal cells of the hippocampus following moderate hypoxic-ischemic brain injury in rats. Brain Res 966:167–174

    Article  PubMed  CAS  Google Scholar 

  8. Basta G (2008) Receptor for advanced glycation end-products and atherosclerosis: from basic mechanism to clinical implication. Atherosclerosis 196:2–9

    Article  Google Scholar 

  9. Koyama H, Yamamoto H, Nishizawa Y (2007) RAGE and soluble RAGE: potential therapeutic targets for cardiovascular diseases. Mol Med 13:625–635

    Article  PubMed  CAS  Google Scholar 

  10. Ding Q, Keller JN (2005) Evaluation of rage isoforms, ligands, and signaling in the brain. Biochim Biophys Acta 1746:18–27

    Article  PubMed  CAS  Google Scholar 

  11. Zhai DX, Kong QF, Xu WS, Bai SS, Peng HS, Zhao K, Li GZ, Wang DD, Sun B, Wang JH, Wang GY, Li HL (2008) RAGE expression is up-regulated in human cerebral ischemia and pMCAO rats. Neurosci Lett 445:117–121

    Article  PubMed  CAS  Google Scholar 

  12. Wang L, Zhang X, Liu L, Yang R, Cui L, Li M (2010) Atorvastatin protects rat brains against permanent focal ischemia and downregulates HMGB1, HMGB1 receptors (RAGE and TLR4) NF-kappaB expression. Neurosci Lett 471:152–156

    Article  PubMed  CAS  Google Scholar 

  13. Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20:84–91

    Article  PubMed  CAS  Google Scholar 

  14. Lizotte PP, Hanford LE, Enghild JJ, Nozik-Grayck E, Giles BL, Oury TD (2007) Developmental expression of the receptor for advanced glycation end-product (RAGE) and its response to hyperoxia in the neonatal rat lung. BMC Dev Biol 7:7–15

    Article  Google Scholar 

  15. Giron MD, Vargas AM, Suarez MD, Salto R (1998) Sequencing of two alternatively spliced mRNAs corresponding to the extracellular domain of the rat receptor for advanced glycosylation end products (RAGE). Biochem Biophys Res Commun 251:230–234

    Article  PubMed  CAS  Google Scholar 

  16. Harashima A, Yamamoto Y, Cheng C, Tsuneyama K, Myint KM, Takeuchi A, Yoshimura K, Li H, Watanabe T, Takasawa S, Okamoto H, Yonekura H, Yamamoto H (2006) Identification of mouse orthologue of endogenous secretory receptor for advanced glycation end-products: structure, function and expression. Biochem J 396:109–115

    Article  PubMed  CAS  Google Scholar 

  17. Qiu J, Nishimura M, Wang Y, Sims JR, Qiu S, Savitz SI, Salomone S, Moskowitz MA (2008) Early release of HMGB-1 from neurons after the onset of brain ischemia. J Cereb Blood Flow Metab 28:927–938

    Article  PubMed  CAS  Google Scholar 

  18. Hassid BG, Nair MN, Ducruet AF, Otten ML, Komotar RJ, Pinsky DJ, Schmidt AM, Yan SF, Connolly ES (2009) Neuronal RAGE expression modulates severity of injury following transient focal cerebral ischemia. J Clin Neurosci 16:302–306

    Article  PubMed  CAS  Google Scholar 

  19. Memezawa H, Minamisawa H, Smith ML, Siesjö BK (1992) Ischemic penumbra in a model of reversible middle cerebral artery occlusion in the rat. Exp Brain Res 89:67–78

    Article  PubMed  CAS  Google Scholar 

  20. Zhang L, Bukulin M, Kojro E, Roth A, Metz VV, Fahrenholz F, Nawroth PP, Bierhaus A, Postina R (2008) Receptor for advanced glycation end products is subjected to protein ectodomain shedding by metalloproteinases. J Biol Chem 283:35507–35516

    Article  PubMed  CAS  Google Scholar 

  21. Amantea D, Corasaniti MT, Mercuri NB, Bernardi G, Bagetta G (2008) Brain regional and cellular localization of gelatinase activity in rat that have undergone transient middle cerebral artery occlusion. Neuroscience 152:8–17

    Article  PubMed  CAS  Google Scholar 

  22. Jiang X, Namura S, Nagata I (2001) Matrix metalloproteinase inhibitor KB-R7785 attenuates brain damage resulting from permanent focal cerebral ischemia in mice. Neurosci Lett 305:41–44

    Article  PubMed  CAS  Google Scholar 

  23. del Zoppo GJ, Milner R, Mabuchi T, Hung S, Wang X, Berg GI, Koziol JA (2007) Microglial activation and matrix protease generation during focal cerebral ischemia. Stroke 38:646–651

    Article  PubMed  Google Scholar 

  24. Fujimura M, Gasche Y, Morita-Fujimura Y, Massengale J, Kawase M, Chan PH (1999) Early appearance of activated matrix metalloproteinase-9 and blood-brain barrier disruption in mice after focal cerebral ischemia and reperfusion. Brain Res 842:92–100

    Article  PubMed  CAS  Google Scholar 

  25. Yao D, Brownlee M (2010) Hyperglycemia-induced reactive oxygen species increase expression of the receptor for advanced glycation end products (RAGE) and RAGE ligands. Diabetes 59:249–255

    Article  PubMed  CAS  Google Scholar 

  26. Matsuda S, Umeda M, Uchida H, Kato H, Araki T (2009) Alterations of oxidative stress markers and apoptosis markers in the striatum after transient focal cerebral ischemia in rats. J Neural Transm 116:395–404

    Article  PubMed  CAS  Google Scholar 

  27. Oliver CN, Starke-Reed PE, Stadtman ER, Liu GJ, Carney JM, Floyd RA (1990) Oxidative damage to brain proteins, loss of glutamine synthetase activity, and production of free radicals during ischemia/reperfusion-induced injury to gerbil brain. Proc Natl Acad Sci USA 87:5144–5147

    Article  PubMed  CAS  Google Scholar 

  28. Chan Ph (2001) Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab 21:2–14

    Article  PubMed  CAS  Google Scholar 

  29. Kontos HA (2001) Oxygen radicals in cerebral ischemia. Stroke 11:2712–2716

    Article  Google Scholar 

  30. Liu S, Liu M, Peterson S, Miyake M, Vallyathan V, Liu KJ (2003) Hydroxyl radical formation is greater in striatal core than in penumbra in a rat model of ischemic stroke. J Neurosci Res 71:882–888

    Article  PubMed  CAS  Google Scholar 

  31. Pichiule P, Chavez JC, Schmidt AM, Vannucci SJ (2007) Hypoxia-inducible factor-1 mediates neuronal expression of the receptor for advanced glycation end products following hypoxia/ischemia. J Biol Chem 282:36330–36340

    Article  PubMed  CAS  Google Scholar 

  32. Galichet A, Weibel M, Heizmann CW (2008) Calcium-regulated intramembrane proteolysis of the RAGE receptor. Biochem Biophys Res Commun 370:1–5

    Article  PubMed  CAS  Google Scholar 

  33. Hanford LE, Enghild JJ, Valnickova Z, Petersen SV, Schaefer LM, Schaefer TM, Reinhart TA, Oury TD (2004) Purification and characterization of mouse soluble receptor for advanced glycation end products (sRAGE). J Biol Chem 279:50019–50024

    Article  PubMed  CAS  Google Scholar 

  34. Chen YS, Yan W, Geczy CL, Brown MA, Thomas R (2009) Serum levels of soluble receptor for advanced glycation endproducts and of S100 proteins are associated with inflammatory, autoantibody, and classical risk markers of joint and vascular damage in rheumatoid arthritis. Arthritis Res Ther 11:R39

    Article  PubMed  Google Scholar 

  35. Stewart C, Cha S, Caudle RM, Berg K, Katz J (2008) Decreased levels of soluble receptor for advanced glycation endproducts in patients with primary Sjogren’s syndrome. Rheumatol Int 28:771–776

    Article  PubMed  CAS  Google Scholar 

  36. Raposeiras-Roubín S, Rodiño-Janeiro BK, Grigorian-Shamagian L, Moure-González M, Seoane-Blanco A, Varela-Román A, Alvarez E, González-Juanatey JR (2010) Soluble receptor of advanced glycation end products levels are related to ischaemic aetiology and extent of coronary disease in chronic heart failure patients, independent of advanced glycation end products levels: new roles for soluble RAGE. Eur J Heart Fail 12:1092–10100

    Article  PubMed  Google Scholar 

  37. Yokota C, Minematsu K, Tomii Y, Naganuma M, Ito A, Nagasawa H, Yamaguchi T (2009) Low levels of plasma soluble receptor for advanced glycation end products are associated with severe leukoaraiosis in acute stroke patients. J Neurol Sci 287(1–2):41–44

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by a grant of the Italian Ministry of Health (Ricerca Corrente 2009) to the IRCCS C. Mondino (C.T.)

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Authors and Affiliations

  1. Laboratory of Neurophysiology of Integrative Autonomic Systems and Headache Science Centre, IRCCS “National Neurological Institute C. Mondino” Foundation and University of Pavia, Via Mondino, 2, 27100, Pavia, Italy

    Rosaria Greco, Antonina Stefania Mangione, Giuseppe Nappi, Fabio Blandini & Cristina Tassorelli

  2. Department of Pharmacobiology, University of Calabria, Arcavacata di Rende, CS, Italy

    Diana Amantea, Francesco Petrelli & Rocco Gentile

  3. University Consortium for Adaptive Disorders and Head Pain (UCADH), Pavia, Rende, CS, Italy

    Diana Amantea, Giuseppe Nappi & Cristina Tassorelli

  4. Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy

    M. Tiziana Corasaniti

Authors
  1. Rosaria Greco
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  2. Diana Amantea
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  3. Antonina Stefania Mangione
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  4. Francesco Petrelli
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  8. M. Tiziana Corasaniti
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  9. Cristina Tassorelli
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Correspondence to Rosaria Greco.

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Greco, R., Amantea, D., Mangione, A.S. et al. Modulation of RAGE Isoforms Expression in the Brain and Plasma of Rats Exposed to Transient Focal Cerebral Ischemia. Neurochem Res 37, 1508–1516 (2012). https://doi.org/10.1007/s11064-012-0778-1

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  • DOI: https://doi.org/10.1007/s11064-012-0778-1

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