Apolipoprotein L1 (APOL1) risk variants greatly elevate the risk of kidney disease in African Americans. Here we report a cohort of patients who developed collapsing focal segmental glomerulosclerosis while receiving therapeutic interferon, all of whom carried the APOL1 high-risk genotype. This finding raised the possibility that interferons and the molecular pattern recognition receptors that stimulate interferon production may contribute to APOL1-associated kidney disease. In cell culture, interferons and toll-like receptor agonists increased APOL1 expression by up to 200-fold, in some cases with the appearance of transcripts not detected under basal conditions. PolyI:C, a double-stranded RNA TLR3 agonist, increased APOL1 expression by upregulating interferons directly or through an interferon-independent, IRF-3 dependent pathway. Using pharmacological inhibitors, shRNA knockdown, and chromatin immunoprecipitation, we found that the interferon-independent TLR3 pathway relied on signaling through TBK1, NF-kB, and Jak kinases, and on binding of IRF1, IRF2, and STAT2 at the APOL1 transcription start site. We also demonstrate that overexpression of the APOL1 risk variants is more injurious to cells than overexpression of the wild-type APOL1 protein. Our study illustrates that anti-viral pathways may be an important inducer of kidney disease in individuals with the APOL1 high-risk genotype and identifies potential targets for prevention or treatment.
Case-control studies suggest that African Americans with genetic variants in both copies of APOL1 have increased risk for hypertension-attributable ESRD and focal segmental glomerulosclerosis. Here, we tested these risk variants in the Dallas Heart Study to ascertain the prevalence of APOL1-associated renal disease in a large population-based study and to estimate the contribution of APOL1 risk variants to disparities in renal disease. We determined the genotype of 1825 African Americans and 1042 European Americans. Among participants without diabetes, we identified microalbuminuria in 2.3% of European Americans, 6.0% of African Americans with no or one APOL1 risk allele, and 16.5% of African Americans with two risk alleles. In addition, the proportions of participants with estimated GFR Ͻ 60 ml/min per 1.73 m 2 was 1.5% for nondiabetic European Americans, 1.7% for African Americans with no or one APOL1 risk allele, and 6.7% for African Americans with two risk alleles. The APOL1 genotype did not associate with any differences in rates of CKD for study participants with diabetes. Our data suggest that more than 3 million African Americans likely have the high-risk genotype and are at markedly increased risk for nondiabetic CKD. In contrast, African Americans without the risk genotype and European Americans appear to have similar risk for developing nondiabetic CKD.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.