Project Summary Chronic kidney disease (CKD), the graduate loss of kidney function, is an incurable condition which affects more than 37 million individuals in the United States and is costly to manage. In particular, Black Americans face a higher risk to develop CKD and progress to end stage kidney disease (ESKD) even after accounting for clinical and socioeconomic factors. Recently, variants in the gene encoding for Apolipoprotein L1 (APOL1) have been identified as risk factors for focal segmental glomerulosclerosis (FSGS) and HIV-associated nephropathy (HIVAN) in individuals with recent African ancestry. However, the cell-specific mechanisms that cause disease are not well understood. In this study we propose to better understand the effect of risk variant APOL1 on macrophage function and inflammation. Specifically, we hypothesize that risk variant APOL1 hinders the macrophage's ability to polarize toward an anti-inflammatory phenotype and thus prolongs inflammation in the kidney after injury. Because APOL1 is found only in humans and new-world primates, we will use induced pluripotent stem cell (iPSC)-derived macrophages to more accurately model native genomic regulation of APOL1. To recapitulate the kidney microenvironment and its effects on macrophage activation, we will induce inflammatory kidney injury in transgenic mice expressing the APOL1 variants. In both iPSC-derived macrophages and transgenic mouse kidney macrophages we will observe the effects of risk variant APOL1 on inflammatory signaling, metabolic activity, and mitochondria-mediated autophagy. We will also evaluate the effect of risk variant APOL1 on anti-inflammatory polarization in macrophages. The goal of this study is to unveil the mechanisms in risk variant APOL1 macrophages which contribute to kidney disease progression.