Intracellular functions of APOL1 in the kidney

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ABSTRACT Chronic kidney disease (CKD) in African Americans is one of the largest racial health disparities in the United States. The cause for the increased risk has been attributed to recessive inheritance of allelic variants in the gene for apolipoprotein L1 (APOL1). These APOL1 variants, known as G1 and G2, do not cause CKD on their own, but CKD is caused by a combination of the inherited genetic risk plus exposure to a triggering environmental stressor. The biological function of APOL1 in the kidney and the mechanism of pathogenesis in the setting of a disease stressor remain unclear. Our recent studies have demonstrated, for the first time, a function for the common APOL1 allele, known as G0, in providing protection against podocyte losses and glomerulosclerosis in one of the CKDs highly associated with carriage of APOL1 risk alleles (HIV-associated nephropathy). The fundamental cause of this protection appears to be linked to a role of APOL1 G0 in supporting innate immune signaling events through pattern recognition receptors. In addition, since APOL1 risk is a recessively inherited trait, this also suggests CKD may be cause, in part, by a loss of this beneficial function. To advance these studies, we propose to develop additional cell-based and animal-based model systems to investigate the function of APOL1 G0 in innate immune responses, and how these responses are altered in the presence of the risk variants G1 and G2. These new cell and animal based systems will allow for both biochemical studies to address mechanism of action and physiological studies to assess impact on CKD progression, and should provide insight into gain- versus loss-of-function mechanisms associated with the recessive inheritance of APOL1 risk alleles. Determining the contribution of G0 function versus risk variant dysfunction will have important clinical impact on further therapy design, as it will establish whether replacement of G0 or suppression of the risk variants would be the more effective strategy.