{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T02:02:37Z","timestamp":1786500157274,"version":"build-2736575974"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2022,4,9]],"date-time":"2022-04-09T00:00:00Z","timestamp":1649462400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,4,9]],"date-time":"2022-04-09T00:00:00Z","timestamp":1649462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The purpose of this study was to design an animal model mimicking glaucoma with hemodynamic instability and to identify involvement of angiotensin II (AngII) and associated changes of the retina. Systemic hypotension was induced in Sprague\u2013Dawley rats by oral hydrochlorothiazide administration. Rats were sacrificed at 4, 8, and 12-week time points. AngII and receptor levels were examined in the serum and retina. To examine the relationship between glia activation and associated RGC death, biochemical analysis of GFAP, Iba-1, and necroptosis associated factors such as TNF\u03b1, receptor-interacting protein (RIP) 1, 3, and inactive caspase 8 were explored. To investigate the difference in RGC death mechanism, JNK inhibitor or RIP3 inhibitor were given intraperitoneally to rats with ocular hypertension and systemic hypotension both to identify the pathway mainly involved. AngII and receptors were increased in the serum and retina of systemic hypotensive rat. At 4, 8, and 12\u2009weeks after hypotension induction, glial activation was increased as indicated by GFAP and Iba-1 staining. TNF\u03b1, RIP3 were elevated. and downregulation of inactive caspase 8 was apparent in the retina of hypotensive rat. Electron microscopy revealed that necroptosis of RGC was gradually increased after systemic hypotension. Following intraperitoneal JNK inhibitor or RIP3 inhibitor administration, RGC loss was attenuated in systemic hypotensive rats but not in ocular hypertensive rats. In conclusion, AngII is involved in glial activation and associated RGC necroptosis following systemic hypotension. This pathway represents a novel and distinct cell death mechanism when compared to that involved in elevated intraocular pressure.<\/jats:p>","DOI":"10.1038\/s41419-022-04762-4","type":"journal-article","created":{"date-parts":[[2022,4,9]],"date-time":"2022-04-09T03:29:04Z","timestamp":1649474944000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Angiotensin II related glial cell activation and necroptosis of retinal ganglion cells after systemic hypotension in glaucoma"],"prefix":"10.1038","volume":"13","author":[{"given":"Soo Ji","family":"Jeon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jungbin","family":"Huh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eojin","family":"Jeong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chan Kee","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4536-5332","authenticated-orcid":false,"given":"Hae Young Lopilly","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,4,9]]},"reference":[{"key":"4762_CR1","doi-asserted-by":"publisher","first-page":"1711","DOI":"10.1016\/S0140-6736(04)16257-0","volume":"363","author":"RN Weinreb","year":"2004","unstructured":"Weinreb RN, Khaw PT. Primary open-angle glaucoma. Lancet (Lond, Engl). 2004;363:1711\u201320.","journal-title":"Lancet (Lond, Engl)"},{"key":"4762_CR2","doi-asserted-by":"publisher","first-page":"1024","DOI":"10.1016\/j.ophtha.2010.10.016","volume":"118","author":"CS Kim","year":"2011","unstructured":"Kim CS, Seong GJ, Lee NH, Song KC. Namil study group KGS. Prevalence of primary open-angle glaucoma in central South Korea the Namil study. Ophthalmology 2011;118:1024\u201330.","journal-title":"Ophthalmology"},{"key":"4762_CR3","first-page":"1641","volume":"111","author":"A Iwase","year":"2004","unstructured":"Iwase A, Suzuki Y, Araie M, Yamamoto T, Abe H, Shirato S, et al. The prevalence of primary open-angle glaucoma in Japanese: the Tajimi Study. Ophthalmology 2004;111:1641\u20138.","journal-title":"Ophthalmology"},{"key":"4762_CR4","doi-asserted-by":"publisher","first-page":"4467","DOI":"10.1167\/iovs.10-6710","volume":"52","author":"F Galassi","year":"2011","unstructured":"Galassi F, Giambene B, Varriale R. Systemic vascular dysregulation and retrobulbar hemodynamics in normal-tension glaucoma. Invest Ophthalmol Vis Sci. 2011;52:4467\u201371.","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"4762_CR5","doi-asserted-by":"crossref","first-page":"1480746","DOI":"10.1155\/2017\/1480746","volume":"2017","author":"E Kosior-Jarecka","year":"2017","unstructured":"Kosior-Jarecka E, Wrobel-Dudzinska D, Lukasik U, Zarnowski T. Ocular and systemic risk factors of different morphologies of scotoma in patients with normal-tension glaucoma. J Ophthalmol. 2017;2017:1480746.","journal-title":"J Ophthalmol"},{"key":"4762_CR6","doi-asserted-by":"publisher","first-page":"173","DOI":"10.3109\/08820538.2013.771202","volume":"28","author":"RC Mudumbai","year":"2013","unstructured":"Mudumbai RC. Clinical update on normal tension glaucoma. Semin Ophthalmol. 2013;28:173\u20139.","journal-title":"Semin Ophthalmol"},{"key":"4762_CR7","doi-asserted-by":"publisher","first-page":"317","DOI":"10.3129\/i08-056","volume":"43","author":"J Flammer","year":"2008","unstructured":"Flammer J, Mozaffarieh M. Autoregulation, a balancing act between supply and demand. Can J Ophthalmol. 2008;43:317\u201321.","journal-title":"Can J Ophthalmol."},{"key":"4762_CR8","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.jstrokecerebrovasdis.2009.04.007","volume":"19","author":"SA Hamed","year":"2010","unstructured":"Hamed SA, Hamed EA, Ezz Eldin AM, Mahmoud NM. Vascular risk factors, endothelial function, and carotid thickness in patients with migraine: relationship to atherosclerosis. J Stroke Cerebrovasc Dis. 2010;19:92\u2013103.","journal-title":"J Stroke Cerebrovasc Dis"},{"key":"4762_CR9","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.autneu.2004.08.012","volume":"116","author":"Z Stoyneva","year":"2004","unstructured":"Stoyneva Z. Laser doppler-recorded venoarteriolar reflex in Raynaud\u2019s phenomenon. Autonomic Neurosci: basic Clin. 2004;116:62\u20138.","journal-title":"Autonomic Neurosci: basic Clin"},{"key":"4762_CR10","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1016\/j.jash.2014.05.014","volume":"8","author":"LG Navar","year":"2014","unstructured":"Navar LG. Physiology: hemodynamics, endothelial function, renin\u2013angiotensin\u2013aldosterone system, sympathetic nervous system. J Am Soc Hypertension. 2014;8:519\u201324.","journal-title":"J Am Soc Hypertension"},{"key":"4762_CR11","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.biopha.2017.07.091","volume":"94","author":"S Patel","year":"2017","unstructured":"Patel S, Rauf A, Khan H, Abu-Izneid T. Renin-angiotensin-aldosterone (RAAS): the ubiquitous system for homeostasis and pathologies. Biomedicine Pharmacother. 2017;94:317\u201325.","journal-title":"Biomedicine Pharmacother."},{"key":"4762_CR12","doi-asserted-by":"publisher","first-page":"116","DOI":"10.3389\/fncel.2018.00116","volume":"12","author":"K Asraf","year":"2018","unstructured":"Asraf K, Torika N, Apte RN, Fleisher-Berkovich S. Microglial activation is modulated by captopril: in vitro and in vivo studies. Front Cell Neurosci. 2018;12:116.","journal-title":"Front Cell Neurosci"},{"key":"4762_CR13","doi-asserted-by":"publisher","first-page":"5282","DOI":"10.1007\/s12035-017-0754-5","volume":"55","author":"SA Bhat","year":"2018","unstructured":"Bhat SA, Goel R, Shukla S, Shukla R, Hanif K. Angiotensin receptor blockade by inhibiting glial activation promotes hippocampal neurogenesis via activation of Wnt\/beta-catenin signaling in hypertension. Mol Neurobiol. 2018;55:5282\u201398.","journal-title":"Mol Neurobiol"},{"key":"4762_CR14","doi-asserted-by":"publisher","first-page":"1038","DOI":"10.1161\/01.RES.0000043501.47934.FA","volume":"91","author":"MC Zimmerman","year":"2002","unstructured":"Zimmerman MC, Lazartigues E, Lang JA, Sinnayah P, Ahmad IM, Spitz DR, et al. Superoxide mediates the actions of angiotensin II in the central nervous system. Circ Res. 2002;91:1038\u201345.","journal-title":"Circ Res"},{"key":"4762_CR15","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1167\/iovs.17-22416","volume":"59","author":"JA Phipps","year":"2018","unstructured":"Phipps JA, Vessey KA, Brandli A, Nag N, Tran MX, Jobling AI, et al. The role of angiotensin II\/AT1 receptor signaling in regulating retinal microglial activation. Invest Ophthalmol Vis Sci. 2018;59:487\u201398.","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"4762_CR16","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1016\/j.brainresbull.2018.09.014","volume":"143","author":"M Wu","year":"2018","unstructured":"Wu M, Xu L, Wang Y, Zhou N, Zhen F, Zhang Y, et al. S100A8\/A9 induces microglia activation and promotes the apoptosis of oligodendrocyte precursor cells by activating the NF-\u03baB signaling pathway. Brain Res Bull. 2018;143:234\u201345.","journal-title":"Brain Res Bull"},{"key":"4762_CR17","doi-asserted-by":"crossref","unstructured":"Thomas CN, Thompson AM, Ahmed Z, Blanch RJ. Retinal ganglion cells die by necroptotic mechanisms in a site-specific manner in a rat blunt ocular injury model. Cells. 2019;8:1517.","DOI":"10.3390\/cells8121517"},{"key":"4762_CR18","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1080\/02713683.2016.1227449","volume":"42","author":"CR Kim","year":"2017","unstructured":"Kim CR, Kim JH, Park HL, Park CK. Ischemia reperfusion injury Triggers TNFalpha Induced-Necroptosis in Rat Retina. Curr Eye Res. 2017;42:771\u20139.","journal-title":"Curr Eye Res"},{"key":"4762_CR19","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1007\/s13167-018-0155-5","volume":"9","author":"T Binggeli","year":"2018","unstructured":"Binggeli T, Schoetzau A, Konieczka K. In glaucoma patients, low blood pressure is accompanied by vascular dysregulation. EPMA J. 2018;9:387\u201391.","journal-title":"EPMA J"},{"key":"4762_CR20","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1016\/j.brainresbull.2009.04.004","volume":"81","author":"TV Johnson","year":"2010","unstructured":"Johnson TV, Tomarev SI. Rodent models of glaucoma. Brain Res Bull. 2010;81:349\u201358.","journal-title":"Brain Res Bull"},{"key":"4762_CR21","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1007\/BF02867388","volume":"18","author":"H Yadav","year":"2003","unstructured":"Yadav H, Singh PK. Effect of thiazide drug compound on the testicular protein and cholesterol contents of albino rat. Indian J Clin Biochem. 2003;18:206\u20138.","journal-title":"Indian J Clin Biochem"},{"key":"4762_CR22","doi-asserted-by":"publisher","first-page":"1483","DOI":"10.1038\/sj.ki.5002564","volume":"72","author":"S Reungjui","year":"2007","unstructured":"Reungjui S, Hu H, Mu W, Roncal CA, Croker BP, Patel JM, et al. Thiazide-induced subtle renal injury not observed in states of equivalent hypokalemia. Kidney Int. 2007;72:1483\u201392.","journal-title":"Kidney Int"},{"key":"4762_CR23","doi-asserted-by":"publisher","first-page":"F625","DOI":"10.1152\/ajprenal.00140.2005","volume":"290","author":"T Nakagawa","year":"2006","unstructured":"Nakagawa T, Hu H, Zharikov S, Tuttle KR, Short RA, Glushakova O, et al. A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Ren Physiol. 2006;290:F625\u201331.","journal-title":"Am J Physiol Ren Physiol"},{"key":"4762_CR24","first-page":"105","volume":"285","author":"MK White","year":"2004","unstructured":"White MK, Cinti C. A morphologic approach to detect apoptosis based on electron microscopy. Methods Mol Biol. 2004;285:105\u201311.","journal-title":"Methods Mol Biol"},{"key":"4762_CR25","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1016\/j.bbrc.2020.04.127","volume":"527","author":"S Miyake","year":"2020","unstructured":"Miyake S, Murai S, Kakuta S, Uchiyama Y, Nakano H. Identification of the hallmarks of necroptosis and ferroptosis by transmission electron microscopy. Biochem Biophys Res Commun. 2020;527:839\u201344.","journal-title":"Biochem Biophys Res Commun"},{"key":"4762_CR26","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1038\/s41586-019-1770-6","volume":"575","author":"M Fritsch","year":"2019","unstructured":"Fritsch M, G\u00fcnther SD, Schwarzer R, Albert M-C, Schorn F, Werthenbach JP, et al. Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis. Nature 2019;575:683\u20137.","journal-title":"Nature"},{"key":"4762_CR27","doi-asserted-by":"publisher","first-page":"1507","DOI":"10.1080\/02713683.2018.1506036","volume":"43","author":"F Lindemann","year":"2018","unstructured":"Lindemann F, Kuerten D, Koch E, Fuest M, Fischer C, Voss A, et al. Blood pressure and heart rate variability in primary open-angle glaucoma and normal tension glaucoma. Curr Eye Res. 2018;43:1507\u201313.","journal-title":"Curr Eye Res"},{"key":"4762_CR28","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1097\/ICU.0b013e3282f3919b","volume":"19","author":"MB Shields","year":"2008","unstructured":"Shields MB. Normal-tension glaucoma: is it different from primary open-angle glaucoma? Curr Opin Ophthalmol. 2008;19:85\u20138.","journal-title":"Curr Opin Ophthalmol"},{"key":"4762_CR29","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1016\/S0002-9394(01)00964-3","volume":"131","author":"S Drance","year":"2001","unstructured":"Drance S, Anderson DR, Schulzer M. Collaborative normal-tension glaucoma study G. Risk factors for progression of visual field abnormalities in normal-tension glaucoma. Am J Ophthalmol. 2001;131:699\u2013708.","journal-title":"Am J Ophthalmol"},{"key":"4762_CR30","doi-asserted-by":"publisher","DOI":"10.1038\/srep43734","volume":"7","author":"NY Lee","year":"2017","unstructured":"Lee NY, Jung Y, Han K, Park CK. Fluctuation in systolic blood pressure is a major systemic risk factor for development of primary open-angle glaucoma. Sci Rep. 2017;7:43734.","journal-title":"Sci Rep."},{"key":"4762_CR31","doi-asserted-by":"publisher","first-page":"318","DOI":"10.3389\/fphar.2019.00318","volume":"10","author":"X Gong","year":"2019","unstructured":"Gong X, Hu H, Qiao Y, Xu P, Yang M, Dang R, et al. The involvement of enin-angiotensin system in lipopolysaccharide-induced behavioral changes, neuroinflammation, and disturbed insulin signaling. Front Pharm. 2019;10:318.","journal-title":"Front Pharm"},{"key":"4762_CR32","doi-asserted-by":"publisher","first-page":"69","DOI":"10.2174\/1872213X12666180703163824","volume":"12","author":"T Baj","year":"2018","unstructured":"Baj T, Seth R. Role of curcumin in regulation of TNF-\u03b1 mediated brain inflammatory responses. Recent Pat Inflamm Allergy Drug Discov. 2018;12:69\u201377.","journal-title":"Recent Pat Inflamm Allergy Drug Discov"},{"key":"4762_CR33","doi-asserted-by":"publisher","first-page":"861231","DOI":"10.1155\/2014\/861231","volume":"2014","author":"G Olmos","year":"2014","unstructured":"Olmos G, Llad\u00f3 J. Tumor necrosis factor alpha: a link between neuroinflammation and excitotoxicity. Mediators Inflamm. 2014;2014:861231.","journal-title":"Mediators Inflamm"},{"key":"4762_CR34","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-018-1235-0","volume":"15","author":"YK Dhuriya","year":"2018","unstructured":"Dhuriya YK, Sharma D. Necroptosis: a regulated inflammatory mode of cell death. J Neuroinflammation. 2018;15:199.","journal-title":"J Neuroinflammation"},{"key":"4762_CR35","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-019-1716-9","volume":"10","author":"AQ Chen","year":"2019","unstructured":"Chen AQ, Fang Z, Chen XL, Yang S, Zhou YF, Mao L, et al. Microglia-derived TNF-alpha mediates endothelial necroptosis aggravating blood brain-barrier disruption after ischemic stroke. Cell Death Dis. 2019;10:487.","journal-title":"Cell Death Dis"},{"key":"4762_CR36","doi-asserted-by":"publisher","first-page":"1358","DOI":"10.1177\/0963689719867285","volume":"28","author":"J Chen","year":"2019","unstructured":"Chen J, Jin H, Xu H, Peng Y, Jie L, Xu D, et al. The neuroprotective effects of necrostatin-1 on subarachnoid hemorrhage in rats are possibly mediated by preventing blood-brain barrier disruption and RIP3-mediated necroptosis. Cell Transpl. 2019;28:1358\u201372.","journal-title":"Cell Transpl"},{"key":"4762_CR37","doi-asserted-by":"publisher","first-page":"107902","DOI":"10.1016\/j.exer.2019.107902","volume":"191","author":"I Rana","year":"2020","unstructured":"Rana I, Suphapimol V, Jerome JR, Talia DM, Deliyanti D, Wilkinson-Berka JL. Angiotensin II and aldosterone activate retinal microglia. Exp Eye Res. 2020;191:107902.","journal-title":"Exp Eye Res"},{"key":"4762_CR38","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1152\/physrev.00042.2016","volume":"98","author":"A Verkhratsky","year":"2018","unstructured":"Verkhratsky A, Nedergaard M. Physiology of astroglia. Physiological Rev. 2018;98:239\u2013389.","journal-title":"Physiological Rev"},{"key":"4762_CR39","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/bs.pbr.2020.07.004","volume":"256","author":"MD Pinazo-Duran","year":"2020","unstructured":"Pinazo-Duran MD, Munoz-Negrete FJ, Sanz-Gonzalez SM, Benitez-Del-Castillo J, Gimenez-Gomez R, Valero-Vello M, et al. The role of neuroinflammation in the pathogenesis of glaucoma neurodegeneration. Prog Brain Res. 2020;256:99\u2013124.","journal-title":"Prog Brain Res"},{"key":"4762_CR40","doi-asserted-by":"crossref","unstructured":"Vernazza S, Tirendi S, Bassi AM, Traverso CE, Sacca SC. Neuroinflammation in primary open-angle glaucoma. J Clin Med. 2020;9:3172.","DOI":"10.3390\/jcm9103172"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-022-04762-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-022-04762-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-022-04762-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T15:00:51Z","timestamp":1669302051000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-022-04762-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,9]]},"references-count":40,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["4762"],"URL":"https:\/\/doi.org\/10.1038\/s41419-022-04762-4","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,9]]},"assertion":[{"value":"31 March 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 March 2022","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 March 2022","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 April 2022","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"323"}}