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Hypoxia-inducible factor (HIF) stabilizers, or HIF prolyl hydroxylase inhibitors (PHIs), are promising candidates for the treatment of CKD-associated anemia. Since hypoxia and angiogenesis are involved in eye diseases, this study examined the effects of HIF-PHIs on metabolism and gene expression in retinal pigment epithelium (RPE) cells. Results revealed that PHIs differentially induced angiogenic (VEGFA, ANG) and glycolytic (PDK1, GLUT1) gene expression, with Roxadustat causing the strongest transcriptional changes. However, Roxadustat-induced angiogenic signals did not promote endothelial tube formation. Moreover, it did not induce oxidative stress, inflammation, or significant antioxidant gene responses in ARPE-19 cells. Roxadustat also reduced the inflammatory cytokine response to tumor necrosis factor-\u03b1, including IL-6, IL-8, and MCP-1, and did not exacerbate VEGF expression under high-glucose conditions. Overall, Roxadustat triggered complex gene expression changes without promoting inflammation or oxidative stress in RPE cells. Despite these findings, ophthalmologic monitoring is advised during PHI treatment in CKD patients receiving HIF-PHIs.<\/jats:p>","DOI":"10.3390\/cells14141121","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T10:35:31Z","timestamp":1753094131000},"page":"1121","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Prolyl Hydroxylase Inhibitor-Mediated HIF Activation Drives Transcriptional Reprogramming in Retinal Pigment Epithelium: Relevance to Chronic Kidney Disease"],"prefix":"10.3390","volume":"14","author":[{"given":"Tam\u00e1s","family":"G\u00e1ll","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Nephrology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"},{"name":"K\u00e1lm\u00e1n Laki Doctoral School, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7549-5691","authenticated-orcid":false,"given":"D\u00e1vid","family":"Peth\u0151","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Nephrology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"},{"name":"K\u00e1lm\u00e1n Laki Doctoral School, University of Debrecen, H-4032 Debrecen, Hungary"},{"name":"HUN-REN\u2013UD Vascular Biology and Myocardium Pathophysiology Research Group, Hungarian Academy of Sciences, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annam\u00e1ria","family":"Nagy","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Nephrology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"},{"name":"K\u00e1lm\u00e1n Laki Doctoral School, University of Debrecen, H-4032 Debrecen, Hungary"},{"name":"HUN-REN\u2013UD Vascular Biology and Myocardium Pathophysiology Research Group, Hungarian Academy of Sciences, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9722-251X","authenticated-orcid":false,"given":"Szil\u00e1rd","family":"P\u00f3liska","sequence":"additional","affiliation":[{"name":"Genomic Medicine and Bioinformatic Core Facility, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gy\u00f6rgy","family":"Balla","sequence":"additional","affiliation":[{"name":"HUN-REN\u2013UD Vascular Biology and Myocardium Pathophysiology Research Group, Hungarian Academy of Sciences, University of Debrecen, H-4032 Debrecen, Hungary"},{"name":"Department of Pediatrics, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7923-2645","authenticated-orcid":false,"given":"J\u00f3zsef","family":"Balla","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Nephrology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"},{"name":"K\u00e1lm\u00e1n Laki Doctoral School, University of Debrecen, H-4032 Debrecen, Hungary"},{"name":"HUN-REN\u2013UD Vascular Biology and Myocardium Pathophysiology Research Group, Hungarian Academy of Sciences, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"KDOQI, and National Kidney Foundation (2006). 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