Hypoxia hits APOL1 in the kidney

Grampp, Steffen; Krüger, René; Lauer, Victoria; Uebel, Sebastian; Knaup, Karl X.; Naas, Julia; Höffken, Verena; Weide, Thomas; Schiffer, Mario; Naas, Stephanie; Schödel, Johannes

doi:10.1016/j.kint.2023.03.035

Cited by 6 publications

(9 citation statements)

References 24 publications

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“…Interestingly, HRE1, HRE2, and HRE4 were located on the sense strand upstream of the APOL1 transcription start site, while HRE5 and HRE6 were situated on the antisense strand. These findings agree with a prior study [ 38 ], reinforcing the notion that HREs within the enhancer region of the APOL1 gene are critical in modulating its expression during hypoxic conditions.…”

Section: Discussionsupporting

confidence: 93%

“…Recent findings suggest that hypoxia stimulates the expression of the APOL1 gene in cultured human podocytes through the interaction of hypoxia-inducible factor (HIF)-1α with a DNA region located approximately 3 kb upstream of the APOL1 promoter [ 38 ]. However, the hypoxia response elements (HREs) responsible for APOL1 expression were not identified.…”

Section: Resultsmentioning

confidence: 99%

“…To explore whether IFI16 regulates HIF-1α binding to HREs, we aimed to identify these elements in the APOL1 gene promoter. Although a prior study identified the HIF-1α-binding region within the enhancer sequence of the APOL1 gene [ 38 ], it did not specify the exact locations of the HREs. Using the genomic sequence from the UCSC Genome Browser (hg38), we identified six potential A/GCGTG HIF-1α-binding motifs (HREs) within an approximately 3 kb region upstream of the APOL1 transcription start site.…”

Section: Discussionmentioning

confidence: 99%

“…HIF-1α is a pivotal regulator of gene expression under hypoxic conditions by selectively binding to the consensus 5 ′ -A/GCGTG-3 ′ sequence, known as hypoxia response elements (HREs), situated within gene promoters or enhancers. A recent identification of an HRE within the enhancer region (coordinates: 36,250,101-36,250,603) of the APOL1 gene using the assay for transposase-accessible chromatin sequencing (ATAC-seq) approach [38] prompted us to explore potential additional HREs in the regulatory elements of the APOL1 gene. Employing the UCSC Genome Browser (hg38), we identified six putative HREs with the consensus 5 ′ -A/GCGTG-3 ′ motifs in the APOL1 gene, covering the promoter/enhancer region of approximately 3 kb.…”

Section: Identification Of Active Hypoxia Response Elements Within Th...mentioning

confidence: 99%

“…A recent study has demonstrated that hypoxia, characterized by low cellular oxygen concentrations, activates APOL1 transcription in kidney podocytes and tubular cells [ 38 ]. This finding aligns with the known role of renal hypoxia in kidney injury and repair and the pathogenesis of CKD and ESRD [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ].…”

Section: Introductionmentioning

confidence: 99%

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IFI16 Is Indispensable for Promoting HIF-1α-Mediated APOL1 Expression in Human Podocytes under Hypoxic Conditions

Randle,

Amara,

Popik

2024

IJMS

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Genetic variants in the protein-coding regions of APOL1 are associated with an increased risk and progression of chronic kidney disease (CKD) in African Americans. Hypoxia exacerbates CKD progression by stabilizing HIF-1α, 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-1α 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-1α. Co-immunoprecipitation assays indicate no direct interaction between IFI16 and HIF-1α. Our studies identify hypoxia response elements (HREs) in the APOL1 gene enhancer/promoter region, showing increased HIF-1α binding to HREs located in the APOL1 gene enhancer. Luciferase reporter assays confirm the role of these HREs in transcriptional activation. Chromatin immunoprecipitation (ChIP)–qPCR assays demonstrate that IFI16 is not recruited to HREs, and IFI16 deletion reduces HIF-1α 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.

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Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Identification Of Active Hypoxia Response Elements Within Th...mentioning

confidence: 99%