{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T23:36:41Z","timestamp":1764113801202,"version":"3.46.0"},"reference-count":35,"publisher":"Georg Thieme Verlag KG","issue":"10","funder":[{"DOI":"10.13039\/501100006122","name":"Deutsche Ophthalmologische Gesellschaft","doi-asserted-by":"crossref","award":["MD grant to Anja Jaeckle (Promotionsstipendium)"],"award-info":[{"award-number":["MD grant to Anja Jaeckle (Promotionsstipendium)"]}],"id":[{"id":"10.13039\/501100006122","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Exp Clin Endocrinol Diabetes"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Sitagliptin, an inhibitor of dipeptidyl peptidase-4 widely used in type 2\n                        diabetes therapy, impairs the barrier formed by retinal endothelial cells\n                        (REC) during prolonged exposure. Because diabetic macular edema is treated\n                        with inhibitors of vascular endothelial growth factor (VEGF)-A signaling, we\n                        now studied (1) if sitagliptin interfered with this therapeutic approach and\n                        (2) if VEGF-A is involved in sitagliptin-induced barrier dysfunction.<\/jats:p>\n                  <jats:p>Confluent immortalized bovine REC (iBREC) were exposed for two days to\n                        sitagliptin and\/or tivozanib, an inhibitor of the VEGF receptor 2, with or\n                        without VEGF-A. The cell index as an indicator of permeability was\n                        continuously measured, and cells and supernatants were harvested.\n                        Expressions of regulators of para- and transcellular flow, i.e., claudin-1,\n                        claudin-5, and plasmalemma vesicle-associated protein (PLVAP), were\n                        determined by subsequent Western blot analyses, and potential secretion of\n                        VEGF-A was measured by ELISA.<\/jats:p>\n                  <jats:p>Sitagliptin-exposed iBREC did not secrete VEGF-A, and, accordingly, tivozanib\n                        did not prevent the sitagliptin-induced decline of the cell index and the\n                        increased expression of tight junction (TJ) protein claudin 1. More\n                        TJ-protein claudin-5 was isolated together with proteins from membranes or\n                        organelles from sitagliptin-treated iBREC, which did not express PLVAP. The\n                            VEGF-A165-induced declines of the cell index and TJ-protein\n                        claudin-1 were prevented by tivozanib, and this process was not modulated by\n                        sitagliptin.<\/jats:p>\n                  <jats:p>The underlying mechanisms of barrier dysfunctions caused by sitagliptin or\n                        VEGF-A are different and independent. Most importantly, the DPP-4 inhibitor\n                        does not interfere with blocking VEGF signaling to correct VEGF-A-dependent\n                        barrier dysfunction.<\/jats:p>","DOI":"10.1055\/a-2708-3562","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T23:34:24Z","timestamp":1764113664000},"page":"477-484","source":"Crossref","is-referenced-by-count":0,"title":["Sitagliptin does not interfere with VEGF-A signaling in retinal\n                    endothelial cells in vitro"],"prefix":"10.1055","volume":"133","author":[{"given":"Lucian","family":"Amthor","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Ulm University Medical\n                    Center, Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anja","family":"Jaeckle","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Ulm University Medical\n                    Center, Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juergen","family":"Kampmeier","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Ulm University Medical\n                    Center, Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Armin","family":"Wolf","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Ulm University Medical\n                    Center, Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matus","family":"Rehak","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Justus Liebig University\n                    Giessen, Giessen, Germany"},{"name":"Department of Ophthalmology, Medical University of\n                    Innsbruck, Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helmut","family":"Deissler","sequence":"additional","affiliation":[{"name":"HD\/U Giessen, Giessen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Focke","family":"Ziemssen","sequence":"additional","affiliation":[{"name":"Center of Ophthalmology, Eberhard Karls University\n                    T\u00fcbingen, Faculty of Medicine, T\u00fcbingen, Germany"},{"name":"Department of Ophthalmology, University Hospital\n                    Leipzig, Leipzig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0086-7811","authenticated-orcid":false,"given":"Heidrun L","family":"Deissler","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Ulm University Medical\n                    Center, Ulm, Germany"},{"name":"Department of Ophthalmology, Justus Liebig University\n                    Giessen, Giessen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"194","published-online":{"date-parts":[[2025,11,25]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/cei.12781","article-title":"Cut to the chase: A review of CD26\/dipeptidyl peptidase-4\u2019s (DPP4) entanglement\n                    in the immune system","volume":"185","author":"C Klemann","year":"2016","journal-title":"Clin Exp Immunol"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1021\/jm0493156","article-title":"(2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine:\n                    A potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of\n                    type 2 diabetes","volume":"48","author":"D Kim","year":"2005","journal-title":"J Med Chem"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"361","DOI":"10.4093\/dmj.2018.0137","article-title":"Dipeptidyl peptidase-4 inhibitor use and risk of diabetic retinopathy: A\n                    population-based study","volume":"44","author":"N H Kim","year":"2018","journal-title":"Diabetes Metab"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"2871","DOI":"10.3390\/jcm10132871","article-title":"Association between add-on dipeptidyl peptidase-4 inhibitor therapy and diabetic\n                    retinopathy progression","volume":"10","author":"EY C Kang","year":"2021","journal-title":"J Clin Med"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"108808","DOI":"10.1016\/j.jdiacomp.2024.108808","article-title":"Dipeptidyl peptidase 4 inhibitors, sodium glucose cotransporter 2 inhibitors,\n                    and glucagon-like peptide 1 receptor agonists do not worsen diabetic macular\n                    edema","volume":"38","author":"A Phu","year":"2024","journal-title":"J Diabetes Complications"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1186\/s12886-024-03535-1","article-title":"Association between dipeptidyl peptidase-4 inhibitor use and diabetic\n                    retinopathy: A systematic review and meta-analysis of real-world studies","volume":"24","author":"M Wang","year":"2024","journal-title":"BMC Ophthalmol"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"1518545","DOI":"10.3389\/fphar.2025.1518545","article-title":"Association of long-term use of dipeptidyl peptidase-4 inhibitors with the risk\n                    of diabetic retinopathy in patients with diabetes mellitus: A real-world\n                    evidence study","volume":"16","author":"Y-C Li","year":"2025","journal-title":"Front Pharmacol"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1016\/j.biopha.2018.03.144","article-title":"The dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin ameliorates retinal\n                    endothelial cell dysfunction triggered by inflammation","volume":"102","author":"A Gon\u00e7alves","year":"2018","journal-title":"Biomed Pharmacother"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"2450781","DOI":"10.1155\/2020\/2450781","article-title":"Sitagliptin and the blood-retina barrier: Effects on retinal endothelial cells\n                    manifested only after prolonged exposure","volume":"2020","author":"A Jaeckle","year":"2020","journal-title":"J Diab Res"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"65","DOI":"10.3892\/ijmm.16.1.65","article-title":"Generation and characterization of iBREC: Novel hTERT-immortalized bovine\n                    retinal endothelial cells","volume":"15","author":"H Deissler","year":"2005","journal-title":"Int J Mol Med"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.ab.2012.03.010","article-title":"A dynamic real-time method for monitoring epithelial barrier function in\n                    vitro","volume":"425","author":"M Sun","year":"2012","journal-title":"Anal Biochem"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"1493","DOI":"10.1159\/000479213","article-title":"Inhibition of single routes of intracellular signaling is not sufficient to\n                    neutralize the biphasic disturbance of a retinal endothelial cell barrier\n                    induced by VEGF-A165","volume":"42","author":"H L Deissler","year":"2017","journal-title":"Cell Physiol Biochem"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"108004","DOI":"10.1016\/j.exer.2020.108004","article-title":"VEGF receptor 2 inhibitor nintedanib completely reverts\n                    VEGF-A165-induced disturbances of barriers formed by retinal\n                    endothelial cells or long-term cultivated ARPE-19 cells","volume":"194","author":"H L Deissler","year":"2020","journal-title":"Exp Eye Res"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"108945","DOI":"10.1016\/j.exer.2022.108945","article-title":"Blocking of VEGF-A is not sufficient to completely revert its long-term effects\n                    on the barrier formed by retinal endothelial cells","volume":"216","author":"H L Deissler","year":"2022","journal-title":"Exp Eye Res"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"8232","DOI":"10.1167\/iovs.14-14217","article-title":"Modulation of VEGF-induced retinal vascular permeability by peroxisome\n                    proliferator-activated receptor-\u03b2\/\u03b4","volume":"55","author":"S Suarez","year":"2014","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/j.exer.2011.12.003","article-title":"A novel co-culture model of the blood-retinal barrier based on primary retinal\n                    endothelial cells, pericytes and astrocytes","volume":"96","author":"J Wisniewska-Kruk","year":"2012","journal-title":"Exp Eye Res"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"3101","DOI":"10.2147\/IJN.S108452","article-title":"Therapeutic effect of apatinib-loaded nanoparticles on diabetes-induced retinal\n                    vascular leakage","volume":"11","author":"J H Jeong","year":"2016","journal-title":"Int J Nanomedicine"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1480","DOI":"10.1056\/NEJM199412013312203","article-title":"Vascular endothelial growth factor in ocular fluid of patients with diabetic\n                    retinopathy and other retinal disorders","volume":"331","author":"L P Aiello","year":"1994","journal-title":"N Engl J Med"},{"key":"ref19","first-page":"2408","article-title":"VEGF-initiated blood-retinal barrier breakdown in early diabetes","volume":"42","author":"T Qaum","year":"2001","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1056\/NEJMoa1414264","article-title":"Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or\n                    ranibizumab for diabetic macular edema","volume":"372","author":"J A Wells","year":"2015","journal-title":"N Engl J Med"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"9134","DOI":"10.1158\/0008-5472.CAN-05-4290","article-title":"KRN951, a highly potent inhibitor of vascular endothelial growth factor receptor\n                    tyrosine kinases, has antitumor activities and affects functional vascular\n                    properties","volume":"66","author":"K Nakamura","year":"2006","journal-title":"Cancer Res"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"12493","DOI":"10.1038\/s41598-022-16770-7","article-title":"Beovu, but not Lucentis impairs the function of the barrier formed by retinal\n                    endothelial cells in vitro","volume":"12","author":"H L Deissler","year":"2022","journal-title":"Sci Rep"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1044","DOI":"10.1016\/j.ajpath.2015.11.019","article-title":"Plasmalemma vesicle-associated protein has a key role in blood-retinal barrier\n                    loss","volume":"186","author":"J Wisniewska-Kruk","year":"2016","journal-title":"Am J Pathol"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"21436","DOI":"10.1038\/s41598-023-46893-4","article-title":"Differential roles of eNOS in late effects of VEGF\u2011A on hyperpermeability in\n                    different types of endothelial cells","volume":"13","author":"E K Bosma","year":"2023","journal-title":"Sci Rep"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"e06037","DOI":"10.1016\/j.heliyon.2021.e06037","article-title":"Type of culture medium determines properties of cultivated retinal endothelial\n                    cells: Induction of substantial phenotypic conversion by standard DMEM","volume":"7","author":"C Busch","year":"2021","journal-title":"Heliyon"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1016\/j.cyto.2013.08.00","article-title":"Norepinephrine and adenosine-5'-triphosphate synergize in inducing IL-6\n                    production by human dermal microvascular endothelial cells","volume":"64","author":"L L Strohl","year":"2013","journal-title":"Cytokine"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1161\/ATVBAHA.112.300893","article-title":"Claudin-5 controls intercellular barriers of human dermal microvascular but not\n                    human umbilical vein endothelial cells","volume":"33","author":"M S Kluger","year":"2014","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1124\/jpet.107.135723","article-title":"(R)-8-(3-Amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione\n                    (BI 1356), a novel xanthine-based dipeptidyl peptidase-4 inhibitor, has a\n                    superior potency and longer duration of action compared with other dipeptidyl\n                    peptidase-4 inhibitors","volume":"325","author":"L Thomas","year":"2008","journal-title":"J Pharmacol Exp Ther"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1177\/108057105279635","article-title":"Dynamic monitoring of cell adhesion and spreading on microelectronic sensor\n                    arrays","volume":"10","author":"J M Atienza","year":"2005","journal-title":"J Biomol Screen"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1453","DOI":"10.3724\/abbs.2022142","article-title":"Identification of sitagliptin binding proteins by affinity purification mass\n                    spectrometry","volume":"54","author":"X N Wang","year":"2022","journal-title":"Acta Biochim Biophys Sin"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"e86671","DOI":"10.1371\/journal.pone.0086671","article-title":"CD9 negatively regulates CD26 expression and inhibits CD26-mediated enhancement\n                    of invasive potential of malignant mesothelioma cells","volume":"9","author":"T Okamoto","year":"2014","journal-title":"PLoS One"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"2285","DOI":"10.1007\/s00125-017-4388-y","article-title":"Topical administration of DPP-IV inhibitors prevents retinal neurodegeneration\n                    in experimental diabetes","volume":"60","author":"C Hern\u00e1ndez","year":"2017","journal-title":"Diabetologia"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"571","DOI":"10.3390\/ijms24010571","article-title":"Transcriptomic analysis reveals that retinal neuromodulation is a relevant\n                    mechanism in the neuroprotective effect of sitagliptin in an experimental model\n                    of diabetic retinopathy","volume":"24","author":"H Ramos","year":"2022","journal-title":"Int J Mol Sci"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"2782","DOI":"10.2337\/db09-1606","article-title":"TNF-\u03b1 signals through PKC\u03b6\/NF-\u03baB to alter the tight junction complex and\n                    increase retinal endothelial cell permeability","volume":"59","author":"C A Aveleira","year":"2010","journal-title":"Diabetes"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"2156273","DOI":"10.1155\/2016\/2156273","article-title":"Diabetic macular edema pathophysiology: vasogenic versus inflammatory","volume":"2016","author":"P Romero-Aroca","year":"2016","journal-title":"J Diabetes Res"}],"container-title":["Experimental and Clinical Endocrinology &amp; Diabetes"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/a-2708-3562.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T23:34:24Z","timestamp":1764113664000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/a-2708-3562"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11]]},"references-count":35,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,11,25]]},"published-print":{"date-parts":[[2025,11]]}},"URL":"https:\/\/doi.org\/10.1055\/a-2708-3562","archive":["Portico","CLOCKSS"],"relation":{},"ISSN":["0947-7349","1439-3646"],"issn-type":[{"value":"0947-7349","type":"print"},{"value":"1439-3646","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11]]}}}