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RNA sequencing of isolated cell populations expressing human APOL1 G2 risk variant reveals molecular correlates of sickle cell nephropathy in zebrafish podocytes.

ABSTRACT: Kidney failure occurs in 5-13% of individuals with sickle cell disease and is associated with early mortality. Two APOL1 alleles (G1 and G2) have been identified as risk factors for sickle cell disease nephropathy. Both risk alleles are prevalent in individuals with recent African ancestry and have been associated with nephropathic complications in other diseases. Despite the association of G1 and G2 with kidney dysfunction, the mechanisms by which these variants contribute to increased risk remain poorly understood. Previous work in zebrafish models suggest that the G2 risk allele functions as a dominant negative, whereas the G1 allele is a functional null. To understand better the cellular pathology attributed to APOL1 G2, we investigated the in vivo effects of the G2 risk variant on distinct cell types using RNA sequencing. We surveyed APOL1 G2 associated transcriptomic alterations in podocytes and vascular endothelial cells isolated from zebrafish larvae expressing cell-type specific reporters. Our analysis identified many transcripts (n = 7,523) showing differential expression between APOL1 G0 (human wild-type) and APOL1 G2 exposed podocytes. Conversely, relatively few transcripts (n = 107) were differentially expressed when comparing APOL1 G0 and APOL1 G2 exposed endothelial cells. Pathway analysis of differentially expressed transcripts in podocytes showed enrichment for autophagy associated terms such as "Lysosome" and "Phagosome", implicating these pathways in APOL1 G2 associated kidney dysfunction. This work provides insight into the molecular pathology of APOL1 G2 nephropathy which may offer new therapeutic strategies for multiple disease contexts such as sickle cell nephropathy.

SUBMITTER: Bundy JL

PROVIDER: S-EPMC6546218 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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RNA sequencing of isolated cell populations expressing human APOL1 G2 risk variant reveals molecular correlates of sickle cell nephropathy in zebrafish podocytes.

Bundy Joseph L JL Anderson Blair R BR Francescatto Ludmila L Garrett Melanie E ME Soldano Karen L KL Telen Marilyn J MJ Davis Erica E EE Ashley-Koch Allison E AE

PloS one 20190603 6

Kidney failure occurs in 5-13% of individuals with sickle cell disease and is associated with early mortality. Two APOL1 alleles (G1 and G2) have been identified as risk factors for sickle cell disease nephropathy. Both risk alleles are prevalent in individuals with recent African ancestry and have been associated with nephropathic complications in other diseases. Despite the association of G1 and G2 with kidney dysfunction, the mechanisms by which these variants contribute to increased risk rem ...[more]

PMID: 31158233

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Project description:Rationale & objectiveApolipoprotein L1 (APOL1) high-risk variants are associated with an increased risk for chronic kidney disease (CKD) among African Americans. Less is known regarding the risk for the development of CKD and kidney failure (end-stage kidney disease [ESKD]) among African Americans with only 1 APOL1 risk variant or whether the risk is modified by sickle cell trait.Study designThe Jackson Heart Study is a community-based longitudinal cohort study.Setting & participantsSelf-reported African Americans in the Jackson Heart Study (n = 5,306).ExposuresAPOL1 G1 and G2 genotypes and sickle cell trait.OutcomesIncident CKD (estimated glomerular filtration rate < 60 mL/min/1.73 m2), albuminuria (urinary albumin-creatinine ratio ≥ 30 mg/g), continuous and rapid kidney function decline (≥30% decline), and incident ESKD.Analytical approachMultivariable linear and logistic regression, and Cox proportional hazards models adjusted for age, sex, hypertension, diabetes, ancestry informative markers, and sickle cell trait.ResultsOf 2,300 participants, 41.3% had zero, 45.1% had 1, and 13.6% had 2 APOL1 risk variants. Sickle cell trait was present in 8.5%. Compared with participants with zero APOL1 risk variants, those with 2 alleles had an increased risk for incident albuminuria (adjusted HR [aHR], 1.88; 95% CI, 1.04 to 3.40), ESKD (aHR, 9.05; 95% CI, 1.79 to 45.85), incident CKD (aHR, 1.65; 95% CI, 1.06 to 2.57), continuous decline (β = -1.90; 95% CI, -3.35 to -0.45), and rapid kidney function decline (OR, 2.21; 95% CI, 1.22 to 4.00) after adjustment for sickle cell trait, with similar results after adjustment for ancestry informative markers. Having 1 APOL1 risk variant was not associated with CKD outcomes and there was no interaction of APOL1 with sickle cell trait.LimitationsSingle-site recruitment of African American individuals with APOL1 and sickle cell trait.ConclusionsThe presence of 1 APOL1 risk allele was not associated with increased risk for CKD outcomes, whereas 2 risk alleles were associated with incident albuminuria, CKD, ESKD, and rapid and continuous kidney function decline. Additional studies are needed to determine factors that might alter the risk for adverse kidney outcomes among individuals with high-risk APOL1 genotypes.

Dataset Information

RNA sequencing of isolated cell populations expressing human APOL1 G2 risk variant reveals molecular correlates of sickle cell nephropathy in zebrafish podocytes.

Publications

RNA sequencing of isolated cell populations expressing human APOL1 G2 risk variant reveals molecular correlates of sickle cell nephropathy in zebrafish podocytes.

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