ApoL1 and its kidney disease associated variants: ion permease activity, molecular structure, and podocyte injury.

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Risk of progressive kidney disease is substantially higher in African Americans than in the general population. This increased risk constitutes an enormous burden of disease and a significant public health problem. A recent genetic analysis has shown that most of the racially- associated increased risk is due to genetic variants in the gene encoding ApoL1. These disease-associated variants are common in people of African descent but absent in other populations. ApoL1 was already known to be important in an apparently unrelated disease, African trypanosomiasis. ApoL1 is the factor in human serum than confers resistance to infection by the common African trypanosome. ApoL1 is thought to kill trypanosomes by entering the limiting membrane of the trypanosome endocytic vacuole and functioning as an ion permease. The disease-associated variants of ApoL1 confer resistance to a particularly pathogenic subtype of trypanosome. How these variants exacerbate human kidney diseases is still unknown. Whether “normal” ApoL1 plays a role in kidney disease of non-African populations is also unknown. The central hypothesis of this proposal is that ApoL1 functions in kidney cells in the same way it is toxic to trypanosomes, that is, by inserting into membranes along the endocytic pathway and subsequently acting as an ion channel in situ or after sorting to other compartments such as the plasma membrane; and that variant ApoL1 has cellular toxicity because of alterations in its ion permease activity. We propose to study the ion permease activity, molecular structure, and cellular effects of ApoL1 and its disease-associated variants to look for differences that may explain enhanced disease progression associated with the variants. Successful identification of changes in activity that correlate with cellular toxicity could lead to powerful new approaches to treatment of progressive kidney disease in people who carry the disease-associated variants and perhaps for people who carry wild type ApoL1 as well.