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Genetic Inhibition of APOL1 Pore-Forming Function Prevents APOL1-Mediated Kidney Disease
Adriana M Hung1,2, Victoria A Assimon3, Hua-Chang Chen1,4
1Nashville VA Medical Center, VA Tennessee Valley Healthcare System, Nashville, Tennessee.
Journal of the American Society of Nephrology : JASN
|October 6, 2023
Summary
A newly identified APOL1 variant, p.N264K, significantly reduces the risk of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) in individuals with high-risk APOL1 genotypes. This protective effect offers potential therapeutic targets for APOL1-associated kidney disease.
Area of Science:
- Genetics
- Nephrology
- Pharmacology
Background:
- African Americans have a disproportionately high risk of chronic kidney disease (CKD), partly due to high-risk (HR) variants in the apolipoprotein L1 (APOL1) gene.
- The APOL1 gene plays a crucial role in kidney disease susceptibility, particularly in individuals of African ancestry.
Purpose of the Study:
- To investigate the protective effect of a specific APOL1 variant, p.N264K, against CKD and end-stage kidney disease (ESKD) in individuals carrying APOL1 HR genotypes.
- To explore the functional mechanisms by which APOL1 p.N264K mitigates the risk associated with APOL1 HR variants.
Main Methods:
- A large-scale cross-sectional analysis of 121,492 participants of African ancestry from the Million Veteran Program (MVP), with replication in two additional cohorts.
- Analysis compared the association between APOL1 HR genotypes with and without the p.N264K variant, assessing CKD and ESKD as primary and secondary outcomes.
- Functional studies in cell models were conducted to elucidate the molecular mechanisms of APOL1 p.N264K action.
Main Results:
- In the MVP cohort, APOL1 HR genotypes without p.N264K were associated with significantly increased odds of CKD and ESKD.
- The presence of APOL1 p.N264K markedly mitigated the kidney disease risk associated with APOL1 HR variants, lowering it to levels comparable with low-risk genotypes.
- Replication cohorts confirmed that APOL1 p.N264K significantly reduced the renal risk in carriers of APOL1 HR variants.
Conclusions:
- The APOL1 p.N264K variant acts as a protective factor against CKD and ESKD in individuals with APOL1 HR genotypes.
- APOL1 p.N264K functions by blocking the pore-forming activity and ion channel conduction of APOL1, thereby reducing cellular toxicity.
- These findings suggest that mimicking the protective mechanism of APOL1 p.N264K could lead to novel therapeutic strategies for APOL1-associated kidney diseases.
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