Transcriptome of BAC-transgenic G1- and G0-APOL1 murine CD8+T-cells after ex-vivo stimulation.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE289030 | GEO | 2026/02/06
REPOSITORIES: GEO
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Project description:Transcriptome of BAC-transgenic G1- and G0-APOL1 murine CD8+T-cells after ex-vivo stimulation.
| PRJNA1220669 | ENA
Project description:African Americans develop end-stage renal disease at a higher rate compared to European Americans due to two polymorphisms (G1 and G2 risk variants) in the apolipoprotein L1 (APOL1) gene that are common in people of African ancestry. Not all homozygous risk allele carriers, however, develop renal disease suggesting that modifying factors (“second hits”) are required. Although the compelling genetic evidence provides an exciting opportunity for personalized medicine in chronic kidney disease (CKD), drug discovery efforts have been greatly hindered by the fact that APOL1 expression is limited to humans and select nonhuman primates. We describe a novel physiologically-relevant genomic mouse model of APOL1-associated renal disease that expresses human APOL1 from the endogenous human promoter, resulting in expression in similar tissues and at similar relative levels as humans. While naïve genomic APOL1 transgenic mice did not exhibit a renal disease phenotype, a single administration of IFNγ was sufficient to robustly induce proteinuria only in APOL1 G1 transgenic mice, despite inducing kidney APOL1 expression in both G0 and G1 mice, serving as a clinically-relevant “second hit.” We also report on the discovery of the first APOL1 inhibitor, IONIS-APOL1Rx, a Generation 2.5 antisense oligonucleotide (ASO) targeting APOL1 mRNA. Treatment of APOL1 G1 mice with IONIS-APOL1Rx prior to IFNγ challenge robustly and dose-dependently inhibited kidney and liver APOL1 expression and protected against IFNγ-induced proteinuria, indicating that the disease-relevant cell types are sensitive to ASO treatment. Collectively, these data suggest that IONIS-APOL1Rx may be an effective therapeutic for APOL1 nephropathies and warrants further development.
2018-10-16 | GSE121286 | GEO
Project description:The C-terminal variants G1 and G2 of apolipoprotein L1 (APOL1) confer human resistance to the sleeping sickness parasite Trypanosoma rhodesiense, but also increase the risk of developing kidney disease. APOL1 and APOL3 are death-promoting proteins associated with endoplasmic reticulum and Golgi membranes. We report that in podocytes, either expression of APOL1 devoid of C-terminal helix (APOL1) or deletion of APOL3 (APOL3 KO) induce actomyosin reorganization linked to inhibition of phosphatidylinositol-4-phosphate (PI(4)P) synthesis by the Golgi PI(4)-kinase IIIB (PI4KB). Both APOL1 and APOL3 form K+ channels, but only APOL3 exhibited Ca2+-dependent binding to neuronal calcium sensor-1 (NCS-1), promoting NCS-1/PI4KB interaction that strongly activates PI(4)P synthesis. APOL1 C-terminal deletion or mutations increased APOL1 binding to APOL3, affecting APOL3 interaction with NCS-1. Since podocytes of G1 and G2 patients exhibited an APOL1/APOL3KO-like phenotype, APOL1 C-terminal variants may induce kidney disease by preventing APOL3 from activating PI4KB, resulting in actomyosin reorganization of podocytes.
2020-03-19 | PXD016851 | Pride
Project description:To elucidate pathways whereby apolipoprotein L1 gene (APOL1) G1 and G2 variants facilitate kidney disease in African Americans, human embryonic kidney cells (HEK293) were used to establish doxycycline-inducible (Tet-on) cell lines stably expressing reference APOL1 G0 and its G1 and G2 renal-risk variants. Illumina human HT-12-v4 arrays and Affymetrix HTA 2.0 arrays were employed to generate global gene expression data with doxycycline induction. Significantly altered pathways identified through bioinformatics involved mitochondrial function; results were validated using immunoblotting, immunofluorescence and functional assays. Global gene expression profiles were performed on HEK293 Tet-on G0, G1, G2 and empty vector cells with and without Dox induction using Illumina human HT-12 v4 arrays. Another independent gene expression array system, Affymetrix HTA 2.0, was used to verify the results of Illumina arrays. Pair-wise and pattern-based analyses were applied to detect the mostly impacted pathways due to overexpression and by APOL1 genotypes.
2016-08-23 | E-GEOD-85918 | biostudies-arrayexpress
Project description:To elucidate pathways whereby apolipoprotein L1 gene (APOL1) G1 and G2 variants facilitate kidney disease in African Americans, human embryonic kidney cells (HEK293) were used to establish doxycycline-inducible (Tet-on) cell lines stably expressing reference APOL1 G0 and its G1 and G2 renal-risk variants. Illumina human HT-12-v4 arrays and Affymetrix HTA 2.0 arrays were employed to generate global gene expression data with doxycycline induction. Significantly altered pathways identified through bioinformatics involved mitochondrial function; results were validated using immunoblotting, immunofluorescence and functional assays.
2016-08-23 | GSE85918 | GEO
Project description:To elucidate pathways whereby apolipoprotein L1 gene (APOL1) G1 and G2 variants facilitate kidney disease in African Americans, human embryonic kidney cells (HEK293) were used to establish doxycycline-inducible (Tet-on) cell lines stably expressing reference APOL1 G0 and its G1 and G2 renal-risk variants. Illumina human HT-12-v4 arrays and Affymetrix HTA 2.0 arrays were employed to generate global gene expression data with doxycycline induction. Significantly altered pathways identified through bioinformatics involved mitochondrial function; results were validated using immunoblotting, immunofluorescence and functional assays.
2016-08-23 | GSE85919 | GEO
Project description:APOL1 risk variants are associated with kidney disease in blacks, but the mechanisms of renal injury associated with APOL1 risk variants are unknown. Because APOL1 is unique to humans and some primates, we created transgenic (Tg) mice using the promoter of nephrin-encoding Nphs1 to express the APOL1 reference sequence (G0) or the G2 risk variant in podocytes, establishing Tg lines with a spectrum of APOL1 expression levels. Podocytes from Tg-G0 and Tg-G2 mice did not undergo necrosis, apoptosis, or autophagic cell death in vivo, even in lines with highly expressed transgenes. Further, Tg-G0 and Tg-G2 mice did not develop kidney pathology, proteinuria, or azotemia as of 300 days of age. However, by 200 days of age, Tg-G2 mice had significantly lower podocyte density than age-matched WT and Tg-G0 mice had, a difference that was not evident at weaning. Notably, a pregnancy-associated phenotype that encompassed eclampsia, preeclampsia, fetal/neonatal deaths, and small litter sizes occurred in some Tg-G0 mice and more severely in Tg-G2 mice. Similar to human placenta, placentas of Tg mice expressed APOL1. Overall, these results suggest podocyte depletion could predispose individuals with APOL1 risk genotypes to kidney disease in response to a second stressor, and add to other published evidence associating APOL1 expression with preeclampsia.
| S-EPMC5118487 | biostudies-literature
Project description:African Americans bear a disproportionate burden of hypertension (HTN) and hypertension-attributed chronic kidney disease (H-CKD). The role of Apolipoprotein L1 (APOL1) risk variants (G1 and G2) in these conditions have been proposed, but genetic and observational studies have shown inconsistent results.Here, we investigated the causal role of APOL1 risk variants using patient samples, transgenic animal models, and in vitro cellular experiments.In the human kidney, APOL1 was highly expressed by glomerular podocytes and endothelial cells. Mice with podocyte-specific expression of the APOL1 risk variant (G2APOL1), but not those with the reference allele (G0), developed severe secondary HTN following albuminuria and kidney disease. Mice expressing endothelial-specific G2APOL1 RV developed mild hypertension with aging, which exacerbated following uninephrectomy and a high-salt diet. This condition induced slight alterations in kidney function. In vitro and in vivo experiments demonstrated that the APOL1 risk variant activates the cytosolic nucleotide sensor STING, leading to increased production of endothelin 1. Notably, mice with endothelial-specific STING knock-out or those treated with an endothelin inhibitor were protected from G2APOL1 RV-mediated hypertension. These findings indicate the role of G2APOL1 in HTN development through STING and endothelin 1 activation, offering new precision therapeutics for addressing hypertension in Black communities carrying APOL1 risk variants.
2025-12-17 | GSE283166 | GEO
Project description:Tubulointersitial expression data from human kidney biopsy in African American subjects with glomerulopathies We used microarrays to analyze the transcriptome of African American subjects with glomerulopathies and the association of expression with APOL1 risk alleles (G1 and G2)
2015-07-15 | GSE68126 | GEO
Project description:Glomerular expression data from human kidney biopsy in African American subjects with glomerulopathies We used microarrays to analyze the transcriptome of African American subjects with glomerulopathies and the association of expression with APOL1 risk alleles (G1 and G2)
2015-07-15 | GSE68125 | GEO