Transcriptomic analysis of human podocytes [total RNA]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE194330 | GEO | 2022/12/21
REPOSITORIES: GEO
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Project description:We analyzed the small RNA profiles of human podocyte-like epithelial cells (HUPEC) obtained from urine of two subjects with APOL1 low-risk (G0/G0) genotypes and two subjects with APOL1 high-risk (G1/G2) genotypes.
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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.
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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.
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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.
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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.
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Project description:Next-generation sequencing (NGS) has become an important tool in molecular charactarization of animal models. APOL1 variants are associated with end stage renal disease in African Americans. We developed a mouse model with podocyte specific over expression of APOL1. Differential molecular signatures were identified between the groups by RNA-Sequencing on kidney.
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