Apolipoprotein L-1 renal risk variants form active channels at the plasma membrane driving cytotoxicity

Recently evolved alleles of Apolipoprotein L-1 (APOL1) provide increased
protection against African trypanosome parasites while also significantly
increasing the risk of developing kidney disease in humans. APOL1 protects
against trypanosome infections by forming ion channels within the
parasite, causing lysis. While the correlation to kidney disease is
robust, there is little consensus concerning the underlying disease
mechanism. We show in human cells that the APOL1 renal risk variants have
a population of active channels at the plasma membrane, which results in
an influx of both Na+ and Ca2+. We propose a model wherein APOL1 channel
activity is the upstream event causing cell death, and that the
activate-state, plasma membrane-localized channel represents the ideal
drug target to combat APOL1-mediated kidney disease.