Cell-Specific Inducible Human <i>APOL1</i> Risk Variant Expression in Mice Causes Hypertension and Renal Damage

BACKGROUND: Black people bear a disproportionate burden of hypertension and hypertension-attributed chronic kidney disease. A role of apolipoprotein L1 ( APOL1 ) risk variants (RVs; G1 and G2) in these conditions has been proposed, but genetic and observational studies have shown inconsistent results. METHODS: Here, we investigated the causal role of APOL1 RVs using patient samples, transgenic animal models, and in vitro primary cellular experiments. RESULTS: In the human kidney, APOL1 was highly expressed by glomerular podocytes and endothelial cells. Mice with podocyte-specific expression of the APOL1 RV (G2 APOL1 ), but not those with the reference allele (G0), developed severe secondary hypertension after albuminuria and kidney disease. Mice expressing endothelium-specific G2 APOL1 RVs developed mild hypertension with aging, which was exacerbated after unilateral nephrectomy and subsequent high-salt diet feeding. This condition was associated with a slight alteration in kidney function. In vitro and in vivo experiments demonstrated that the APOL1 RV activates the cytosolic nucleotide sensor STING (stimulator of interferon genes), leading to increased production of endothelin 1. Notably, mice with endothelium-specific STING knockout or those treated with an endothelin inhibitor showed protection from G2 APOL1 RV–mediated hypertension. CONCLUSIONS: These findings indicate a role of G2 APOL1 in hypertension development through STING and endothelin 1 activation, offering new precision therapeutics for addressing hypertension in Black people carrying APOL1 RVs.