Related Experiment Video
Updated: Jun 13, 2026
Transient Expression of Proteins by Hydrodynamic Gene Delivery in Mice
Published on: May 5, 2014
Cell-Specific Inducible Human APOL1 Risk Variant Expression in Mice Causes Hypertension and Renal Damage
Fang Li1,2,3, Bibek Poudel1,2, Magaiver Andrade-Silva1,2
1Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia (F.L., B.P., M.A.-S., J. Wu, A.R., J. Wahba, A.V., C.L., A.A., K.A.K., K.S.).
Insights
Apolipoprotein L1 (APOL1) risk variants contribute to hypertension in Black individuals by activating the STING pathway, leading to increased endothelin 1. This discovery offers new therapeutic targets for hypertension management.
Area of Science:
- Nephrology
- Genetics
- Cardiovascular Disease
Background:
- Black individuals disproportionately experience hypertension and chronic kidney disease.
- The role of apolipoprotein L1 (APOL1) risk variants (RVs) in these conditions is debated due to inconsistent study results.
Purpose of the Study:
- To investigate the causal role of APOL1 RVs in hypertension and kidney disease.
- To elucidate the molecular mechanisms underlying APOL1 RV-associated pathology.
Main Methods:
- Utilized patient samples, transgenic animal models (podocyte-specific and endothelium-specific G2APOL1 expression), and in vitro cellular experiments.
- Examined APOL1 expression in human kidney cells (podocytes and endothelial cells).
- Assessed the impact of STING knockout and endothelin inhibition on hypertension in mouse models.
Main Results:
- Podocyte-specific G2APOL1 expression in mice led to severe hypertension, albuminuria, and kidney disease.
- Endothelium-specific G2APOL1 expression caused age-related hypertension, exacerbated by nephrectomy and high-salt diet.
- APOL1 RVs activate the STING pathway, increasing endothelin 1 production, which mediates hypertension.
- STING knockout or endothelin inhibition protected against G2APOL1-induced hypertension.
Conclusions:
- G2APOL1 contributes to hypertension via STING and endothelin 1 activation.
- Findings suggest APOL1 RVs play a direct causal role in hypertension development.
- Identifies potential precision therapeutic targets for hypertension in individuals with APOL1 RVs.
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 (G2APOL1), but not those with the reference allele (G0), developed severe secondary hypertension after albuminuria and kidney disease. Mice expressing endothelium-specific G2APOL1 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 G2APOL1 RV-mediated hypertension.
Conclusions:
These findings indicate a role of G2APOL1 in hypertension development through STING and endothelin 1 activation, offering new precision therapeutics for addressing hypertension in Black people carrying APOL1 RVs.
