Cell-specific Inducible Human APOL1 Risk Variant Expression Cause Hypertension and Renal Damage

African Americans bear a disproportionate burden of hypertension (HTN) and hypertension-attributed chronic kidney disease (H-CKD). The role of Apolipoprotein L1 (APOL1) risk variants (G1 and G2) in these conditions have been proposed, but genetic and observational studies have shown inconsistent results.Here, we investigated the causal role of APOL1 risk variants using patient samples, transgenic animal models, and in vitro cellular experiments.In the human kidney, APOL1 was highly expressed by glomerular podocytes and endothelial cells. Mice with podocyte-specific expression of the APOL1 risk variant (G2APOL1), but not those with the reference allele (G0), developed severe secondary HTN following albuminuria and kidney disease. Mice expressing endothelial-specific G2APOL1 RV developed mild hypertension with aging, which exacerbated following uninephrectomy and a high-salt diet. This condition induced slight alterations in kidney function. In vitro and in vivo experiments demonstrated that the APOL1 risk variant activates the cytosolic nucleotide sensor STING, leading to increased production of endothelin 1. Notably, mice with endothelial-specific STING knock-out or those treated with an endothelin inhibitor were protected from G2APOL1 RV-mediated hypertension. These findings indicate the role of G2APOL1 in HTN development through STING and endothelin 1 activation, offering new precision therapeutics for addressing hypertension in Black communities carrying APOL1 risk variants. Overall design: We performed unilateral nephrectomy (UNX) surgery on WT, EC/G0APOL1, and EC/G2APOL1 mice at 6 weeks of age and maintained them on a high salt (4% salt) diet following the surgery.