{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T16:44:03Z","timestamp":1790959443094,"version":"4.1.0"},"reference-count":54,"publisher":"American Physiological Society","issue":"9","funder":[{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["P01-HL144454."],"award-info":[{"award-number":["P01-HL144454."]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.physiology.org"],"crossmark-restriction":true},"short-container-title":["Physiological Genomics"],"published-print":{"date-parts":[[2021,9,1]]},"abstract":"<jats:p> Intermittent hypoxia (IH) is a hallmark manifestation of obstructive sleep apnea (OSA). Rodents treated with IH exhibit hypertension. Hypoxia-inducible factor (HIF)-1-dependent transcriptional activation of NADPH oxidases ( Nox) and the resulting increase in reactive oxygen species (ROS) levels is a major molecular mechanism underlying IH\/OSA-induced hypertension. Jumanji C (JmjC)-containing histone lysine demethylases (JmjC-KDMs) are coactivators of HIF-1-dependent transcriptional activation. In the present study, we tested the hypothesis that JmjC-KDMs are required for IH-evoked HIF-1 transcriptional activation of Nox4 and the ensuing hypertension. Studies were performed on pheochromocytoma (PC)12 cells and rats. IH increased KDM6B protein and enzyme activity in PC12 cells in an HIF-1-independent manner as evidenced by unaltered KDM6B activation by IH in HIF-1\u03b1 shRNA-treated cells. Cells treated with IH showed increased HIF-1-dependent Nox4 transcription as indicated by increased HIF-1\u03b1 binding to hypoxia-responsive element (HRE) sequence of the Nox4 gene promoter demonstrated by chromatin immunoprecipitation (ChiP) assay. Pharmacological blockade of KDM6B with GSKJ4, a specific KDM6 inhibitor, or genetic silencing of KDM6B with shRNA abolished IH-induced Nox4 transcriptional activation by blocking HIF-1\u03b1 binding to the promoter of the Nox4 gene. Treating IH-exposed rats with GSKJ4 showed: 1) absence of KDM6B activation and HIF-1-dependent Nox4 transcription in the adrenal medullae, and 2) absence of elevated plasma catecholamines and hypertension. Collectively, these findings indicate that KDM6B functions as a coactivator of HIF-1-mediated Nox4 transactivation and demonstrates a hitherto uncharacterized role for KDMs in IH-induced hypertension by HIF-1. <\/jats:p>","DOI":"10.1152\/physiolgenomics.00045.2021","type":"journal-article","created":{"date-parts":[[2021,7,23]],"date-time":"2021-07-23T16:09:47Z","timestamp":1627056587000},"page":"385-394","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["Lysine demethylase KDM6B regulates HIF-1\u03b1-mediated systemic and cellular responses to intermittent hypoxia"],"prefix":"10.1152","volume":"53","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3984-7447","authenticated-orcid":true,"given":"Jayasri","family":"Nanduri","sequence":"first","affiliation":[{"name":"Institute for Integrative Physiology and Center for Systems Biology of O2 Sensing, The University of Chicago, Chicago, 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