Genetic variants of apolipoprotein L1 (APOL1) are associated with an increased risk of kidney disease in African Americans. Now, researchers have found that interferons and Toll-like receptor (TLR) agonists significantly increase APOL1 expression and stimulate the appearance of new APOL1 transcript variants. They say their study shows that antiviral pathways might trigger the onset of kidney disease in susceptible individuals who express the high-risk APOL1 variants, and identifies potential therapeutic targets for the treatment of APOL1-associated kidney disease.

To investigate the potential contribution of interferons to APOL1-associated kidney disease, Brendan Nichols and colleagues first assessed APOL1 genotype in biopsy samples from a cohort of patients who had developed collapsing glomerulopathy following interferon treatment; all were found to carry the APOL1 high-risk genotype. Transfection of HEK293 cells with wild-type APOL1 and the APOL1 risk alleles, demonstrated that the risk variants were toxic to cells when expressed at high levels.

The researchers then assessed the ability of interferons to upregulate APOL1 in cultured endothelial cells and podocytes. In both cell types, IFN-α, IFN-β and IFN-γ stimulated APOL1 expression. Interferon exposure also resulted in the appearance of two APOL1 transcript variants. Administration of a double-stranded RNA mimic and TLR3 agonist to cultured cells also increased APOL1 expression. Further experiments identified two distinct pathways regulating APOL1 expression: one involving classical interferon signalling, and an interferon-independent TLR3 pathway involving TBK1, NFκB and Jak kinases.