Endoplasmic Reticulum Stress and Macrophage Function in APOL1 Nephropathy

In the United States, patients with African ancestry have a disproportionately high risk of developing chronic kidney disease (CKD) that progresses to end-stage kidney disease. Driving much of this risk are two common coding variants, termed G1 and G2, in the APOL1 gene encoding innate immunity factor apolipoprotein L1 (APOL1). A subset of patients carrying two risk alleles develops APOL1 nephropathy, a spectrum of kidney disease phenotypes including collapsing glomerulopathy in HIV and COVID-19 patients. However, the precise mechanisms by which these variants cause CKD remain unclear. Prior studies have focused on podocyte injury, but potential pathogenic roles of other APOL1-expressing cell types relevant to innate immunity are unknown. Macrophages, which express APOL1 in response to inflammatory stimuli, contribute to CKD development when their roles in tissue homeostasis and injury response are dysregulated. The goal of this proposal is to elucidate the mechanisms by which APOL1 risk variants alter macrophage function, resulting in failed resolution of tissue inflammation and the promotion of kidney fibrosis.