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Hypoxia exacerbates CKD progression by stabilizing HIF-1\u03b1, which induces APOL1 transcription in kidney podocytes. However, the contribution of additional mediators to regulating APOL1 expression under hypoxia in podocytes is unknown. Here, we report that a transient accumulation of HIF-1\u03b1 in hypoxia is sufficient to upregulate APOL1 expression in podocytes through a cGAS\/STING\/IRF3-independent pathway. Notably, IFI16 ablation impedes hypoxia-driven APOL1 expression despite the nuclear accumulation of HIF-1\u03b1. Co-immunoprecipitation assays indicate no direct interaction between IFI16 and HIF-1\u03b1. Our studies identify hypoxia response elements (HREs) in the APOL1 gene enhancer\/promoter region, showing increased HIF-1\u03b1 binding to HREs located in the APOL1 gene enhancer. Luciferase reporter assays confirm the role of these HREs in transcriptional activation. Chromatin immunoprecipitation (ChIP)\u2013qPCR assays demonstrate that IFI16 is not recruited to HREs, and IFI16 deletion reduces HIF-1\u03b1 binding to APOL1 HREs. RT-qPCR analysis indicates that IFI16 selectively affects APOL1 expression, with a negligible impact on other hypoxia-responsive genes in podocytes. These findings highlight the unique contribution of IFI16 to hypoxia-driven APOL1 gene expression and suggest alternative IFI16-dependent mechanisms regulating APOL1 gene expression under hypoxic conditions.<\/jats:p>","DOI":"10.3390\/ijms25063324","type":"journal-article","created":{"date-parts":[[2024,3,15]],"date-time":"2024-03-15T09:32:30Z","timestamp":1710495150000},"page":"3324","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["IFI16 Is Indispensable for Promoting HIF-1\u03b1-Mediated APOL1 Expression in Human Podocytes under Hypoxic Conditions"],"prefix":"10.3390","volume":"25","author":[{"given":"Richaundra K.","family":"Randle","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, School of Graduate Studies, Meharry Medical College, Nashville, TN 37208, USA"},{"name":"Center for AIDS Health Disparities Research, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venkateswara Rao","family":"Amara","sequence":"additional","affiliation":[{"name":"Center for AIDS Health Disparities Research, Meharry Medical College, Nashville, TN 37208, USA"},{"name":"Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research, Hajipur 844102, Bihar, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waldemar","family":"Popik","sequence":"additional","affiliation":[{"name":"Center for AIDS Health Disparities Research, Meharry Medical College, Nashville, TN 37208, USA"},{"name":"Department of Internal Medicine, School of Medicine, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"25576","DOI":"10.1074\/jbc.272.41.25576","article-title":"Apolipoprotein L, a new human high density lipoprotein apolipoprotein expressed by the pancreas. 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