ArticleProceedings of the National Academy of Sciences of the United States of America2016
APOL1 kidney disease risk variants cause cytotoxicity by depleting cellular potassium and inducing stress-activated protein kinases.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 149 papers, 2 of them syntheses that pooled it.
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Who cites it
149 citing papers in PubMed, 2 syntheses or guidelines pooled it, 232 citations in OpenAlex.
- Apolipoprotein L1 gene variants and kidney disease in patients with HIV: a systematic review and meta-analysis.Journal of nephrology · 2023Pooled it
- Kidney disease in the setting of HIV infection: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.Kidney international · 2018Guideline
- Expression of APOL1 and NOTCH2 genes in patients with type 2 diabetes mellitus attending babcock University Teaching Hospital, Ogun State, Nigeria.Scientific reports · 2026Article
- Apolipoproteins L involvement in immunity.Journal of human immunity · 2026Review
- Potassium and the kidney.Nature reviews. Nephrology · 2026Review
- The APOL1 variant p.N264K is predicted to block ion flow by occluding a pore at the cell surface.Life science alliance · 2026Article
- Molecular Mechanisms of APOL1-Associated Kidney Disease.International journal of molecular sciences · 2026Review
- Article
- A multiplex allele-specific polymerase chain reaction assay for rapid and affordable detection of APOL1 risk variants.Scientific reports · 2026Article
- APOL1 plasma membrane pools resist rapid protein degradation.Scientific reports · 2026Article
- Collapsing FSGS in a kidney transplant with a single APOL1 risk variant: a case report.BMC nephrology · 2026Article
- Unlocking Ethiopia's genomic landscape and its global significance: a call for inclusive genomics research.Human genomics · 2026Review
- The Role of APOL1 in Necrotizing Enterocolitis and Its Promise as a Diagnostic Biomarker.Mediators of inflammation · 2026Article
- APOL1-mediated kidney disease: a narrative review of the lessons learnt from the past 15 years.BMC nephrology · 2025Review
- A novelRenal failure · 2025Article
- Modelling APOL1-mediated kidney inflammation and fibrosis using a partially reprogrammed urine-derived SIX2-positive renal progenitor cell line.Stem cell research & therapy · 2025Article
- APOL1 kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.Kidney international · 2025Article
- Apolipoproteins in Chronic Kidney Disease and Kidney Transplant: A Long Unfinished Story.International journal of molecular sciences · 2025Review
- Review
- Article
89 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
Two specific genetic variants of the apolipoprotein L1 (APOL1) gene are responsible for the high rate of kidney disease in people of recent African ancestry. Expression in cultured cells of these APOL1 risk variants, commonly referred to as G1 and G2, results in significant cytotoxicity. The underlying mechanism of this cytotoxicity is poorly understood. We hypothesized that this cytotoxicity is mediated by APOL1 risk variant-induced dysregulation of intracellular signaling relevant for cell survival. To test this hypothesis, we conditionally expressed WT human APOL1 (G0), the APOL1 G1 variant, or the APOL1 G2 variant in human embryonic kidney cells (T-REx-293) using a tetracycline-mediated (Tet-On) system. We found that expression of either G1 or G2 APOL1 variants increased apparent cell swelling and cell death compared with G0-expressing cells. These manifestations of cytotoxicity were preceded by G1 or G2 APOL1-induced net efflux of intracellular potassium as measured by X-ray fluorescence, resulting in the activation of stress-activated protein kinases (SAPKs), p38 MAPK, and JNK. Prevention of net K(+) efflux inhibited activation of these SAPKs by APOL1 G1 or G2. Furthermore, inhibition of SAPK signaling and inhibition of net K(+) efflux abrogated cytotoxicity associated with expression of APOL1 risk variants. These findings in cell culture raise the possibility that nephrotoxicity of APOL1 risk variants may be mediated by APOL1 risk variant-induced net loss of intracellular K(+) and subsequent induction of stress-activated protein kinase pathways.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.