The discovery that two common APOL1 alleles were strongly associated with nondiabetic kidney diseases in African descent populations led to hope for improved diagnosis and treatment. Unfortunately, we still do not have a clear understanding of the biological function played by APOL1 in podocytes or other kidney cells, nor how the renal risk alleles initiate the development of nephropathies. Important clues for APOL1 function may be gleaned from the natural defense mechanism of APOL1 against trypanosome infections and from similar proteins (e.g., diphtheria toxin, mammalian Bcl-2 family members). This review provides an update on the biological functions for circulating (trypanosome resistance) and intracellular (emerging role for autophagy) APOL1. Further, we introduce a multimer model for APOL1 in kidney cells that reconciles the gain-of-function variants with the recessive inheritance pattern of APOL1 renal risk alleles.
