{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:22:06Z","timestamp":1785424926900,"version":"3.56.0"},"posted":{"date-parts":[[2025,8,19]]},"group-title":"Physiology","reference-count":67,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T00:00:00Z","timestamp":1755561600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["T32EY024234"],"award-info":[{"award-number":["T32EY024234"]}],"id":[{"id":"https:\/\/ror.org\/03wkg3b53","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01EY022076"],"award-info":[{"award-number":["R01EY022076"]}],"id":[{"id":"https:\/\/ror.org\/03wkg3b53","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01EY031817"],"award-info":[{"award-number":["R01EY031817"]}],"id":[{"id":"https:\/\/ror.org\/03wkg3b53","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P30EY014800"],"award-info":[{"award-number":["P30EY014800"]}],"id":[{"id":"https:\/\/ror.org\/03wkg3b53","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/04drjs621","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Crandall Glaucoma Initiative"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,8,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Clinicians are often forced into the dilemma of whether to battle ocular inflammation or preserve vision imperiled by elevated intraocular pressure (IOP). Anti-inflammatory treatments utilizing glucocorticosteroid regimens may induce glaucoma by chronically elevating IOP via increased trabecular meshwork (TM) resistance to the flow of aqueous humor, but it is not known whether pressure transduction itself is impacted by steroids and how changes in TM mechanosignaling affect conventional outflow resistance and IOP. To address this, we investigated the role of TREK-1 (TWIK-related potassium channel-1), a mechanosensitive K\n                  <jats:sup>+<\/jats:sup>\n                  channel, in regulation of outflow facility, transmembrane signaling and dexamethasone (DEX)-induced ocular hypertension (OHT). The expression of tandem-pore potassium channels in mouse TM cells was dominated by\n                  <jats:italic>Trek-1 (Kcnk2<\/jats:italic>\n                  ) mRNA, with residual expression of\n                  <jats:italic>Traak, Tresk2<\/jats:italic>\n                  and\n                  <jats:italic>Twik3<\/jats:italic>\n                  and vanishingly low levels of\n                  <jats:italic>Task1 and Trek2<\/jats:italic>\n                  . DEX suppressed\n                  <jats:italic>Trek1<\/jats:italic>\n                  transcription by \u223c80% but did not affect expression of\n                  <jats:italic>Trpv4<\/jats:italic>\n                  and\n                  <jats:italic>Piezo1<\/jats:italic>\n                  genes. Chronic DEX administration depolarized the membrane potential of TM cells and elevated IOP in mice whereas the selective TREK-1 agonist ML-402 lowered IOP in rodent OHT models. ML-402 doubled the outflow facility in perfused mouse eyes at all applied pressures and hyperpolarized DEX-treated TM cells. These\n                  <jats:italic>in vitro, ex vivo<\/jats:italic>\n                  and\n                  <jats:italic>in vivo<\/jats:italic>\n                  results implicate TREK-1 channels in homeostatic regulation of TM mechanosignaling, conventional outflow regulation and IOP homeostasis. Suppression of TREK-1 signaling by corticosteroids underlies OHT and could contribute to steroid glaucoma but this can be obviated by pharmacological stimulation of the channel with cornea-permeant ML-402 eye drops.\n                <\/jats:p>","DOI":"10.1101\/2025.08.14.670390","type":"posted-content","created":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T14:30:21Z","timestamp":1755613821000},"source":"Crossref","is-referenced-by-count":1,"title":["Corticosteroids elevate intraocular pressure through suppression of TREK-1 signaling"],"prefix":"10.64898","author":[{"given":"Sarah N.","family":"Redmon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8215-7444","authenticated-orcid":false,"given":"Oleg","family":"Yarishkin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher N.","family":"Rudzitis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Lakk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacques","family":"Bertrand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4402-9767","authenticated-orcid":false,"given":"Joseph","family":"van Batenburg-Sherwood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina M.","family":"Nicou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher L.","family":"Passaglia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darryl R.","family":"Overby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4468-3029","authenticated-orcid":false,"given":"David","family":"Kri\u017eaj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025082205001152000_2025.08.14.670390v1.1","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1152\/physrev.00021.2023","article-title":"Glucocorticoids, their uses, sexual dimorphisms, and diseases: new concepts, mechanisms, and discoveries","volume":"104","year":"2024","journal-title":"Physiol Rev"},{"key":"2025082205001152000_2025.08.14.670390v1.2","doi-asserted-by":"publisher","DOI":"10.1001\/archopht.1963.00960050494011"},{"key":"2025082205001152000_2025.08.14.670390v1.3","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.survophthal.2020.01.002","article-title":"Steroid-induced glaucoma: Epidemiology, pathophysiology, and clinical management","volume":"65","year":"2020","journal-title":"Surv Ophthalmol"},{"key":"2025082205001152000_2025.08.14.670390v1.4","doi-asserted-by":"crossref","first-page":"481","DOI":"10.2147\/OPTH.S442749","article-title":"Glucocorticoid-Induced Ocular Hypertension and Glaucoma","volume":"18","year":"2024","journal-title":"Clin Ophthalmol"},{"key":"2025082205001152000_2025.08.14.670390v1.5","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1080\/19336950.2019.1618149","article-title":"Mechano-electrical transduction in trabecular meshwork involves parallel activation of TRPV4 and TREK-1 channels","volume":"13","year":"2019","journal-title":"Channels (Austin)"},{"key":"2025082205001152000_2025.08.14.670390v1.6","unstructured":"D. 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