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

Abstract

Black people bear a disproportionate burden of hypertension and hypertension-attributed chronic kidney disease. A role of apolipoprotein L1 (<i>APOL1</i>) risk variants (RVs; G1 and G2) in these conditions has been proposed, but genetic and observational studies have shown inconsistent results. Here, we investigated the causal role of <i>APOL1</i> RVs using patient samples, transgenic animal models, and in vitro primary cellular experiments. In the human kidney, APOL1 was highly expressed by glomerular podocytes and endothelial cells. Mice with podocyte-specific expression of the <i>APOL1</i> RV (G2<i>APOL1</i>), but not those with the reference allele (G0), developed severe secondary hypertension after albuminuria and kidney disease. Mice expressing endothelium-specific G2<i>APOL1</i> 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 <i>APOL1</i> 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<i>APOL1</i> RV-mediated hypertension. These findings indicate a role of G2<i>APOL1</i> in hypertension development through STING and endothelin 1 activation, offering new precision therapeutics for addressing hypertension in Black people carrying <i>APOL1</i> RVs.