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

被引:2
|
作者
Randle, Richaundra K. [1 ,2 ]
Amara, Venkateswara Rao [2 ,3 ]
Popik, Waldemar [2 ,4 ]
机构
[1] Meharry Med Coll, Sch Grad Studies, Dept Biomed Sci, Nashville, TN 37208 USA
[2] Meharry Med Coll, Ctr AIDS Hlth Dispar Res, Nashville, TN 37208 USA
[3] Natl Inst Pharmaceut Educ & Res, Dept Regulatory Toxicol, Hajipur 844102, Bihar, India
[4] Meharry Med Coll, Sch Med, Dept Internal Med, Nashville, TN 37208 USA
基金
美国国家卫生研究院;
关键词
podocytes; nephropathy; hypoxia; HIF-1; alpha; hypoxia response element (HRE); APOL1; IFI16; chromatin immunoprecipitation (ChIP); FOCAL SEGMENTAL GLOMERULOSCLEROSIS; RISK VARIANTS; KIDNEY-DISEASE; TRYPANOLYTIC FACTOR; AFRICAN-AMERICANS; INDUCIBLE PROTEIN; APOLIPOPROTEIN L; GENE; DNA; NEPHROPATHY;
D O I
10.3390/ijms25063324
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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-1 alpha, 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 alpha 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 alpha. Co-immunoprecipitation assays indicate no direct interaction between IFI16 and HIF-1 alpha. Our studies identify hypoxia response elements (HREs) in the APOL1 gene enhancer/promoter region, showing increased HIF-1 alpha 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-1 alpha 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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页数:22
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