Differential regulation of basal and interferon-induced APOL1 gene expression in podocytes.

APOL1 genetic variants associated with kidney disease become pathogenic when APOL1 gene expression is induced to high levels, however, the mechanism of APOL1 gene regulation is not well characterized. Using human podocyte cell lines, the induction of APOL1 gene expression from various pathogen recognition receptors was universally blocked with a soluble receptor for type I interferons, indicating APOL1 induction from these different innate immune mechanisms was secondary to autocrine production of type I interferon. ATAC-seq and chromatin immunoprecipitations identified the APOL1 gene is regulated by an ISRE-containing promoter and an intronic enhancer containing an interferon-γ activation sequence (GAS) element which explains its responsiveness to both type I and type II interferons. RNAi-mediated gene silencing identified the transcription factor required for basal APOL1 expression levels (IRF1) was not required for interferon-induced expression, which utilized additional transcription factors known to mediate interferon receptor signaling (IRF9 and STATs). An inhibitor of Janus Kinases (JAK), which activate signaling from interferon receptors, was able to attenuate the interferon-induced, but not basal levels of APOL1 expression. These differential gene regulatory mechanism may be useful in optimizing treatment strategies for APOL1 mediated kidney disease.