Kidney Week

Abstract: TH-PO207

Endothelial Cell-Specific Inducible G2APOL1 Risk Variant Induces Hypertension and Hypertensive Kidney Damage

Session Information

• Hypertension and CVD: Basic Research Findings
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

• 1601 Hypertension and CVD: Basic

Authors

• Li, Fang, Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Fang Li, MD, PhD

• Wu, Junnan, Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Junnan Wu, MD

• Kloetzer, Konstantin A., Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Konstantin A. Kloetzer, MD

• Susztak, Katalin, Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Katalin Susztak, MD, PhD

Background

GWAS showed a strong association between the apolipoprotein1 (APOL1) gene and hypertension in AA adults. Nearly 45% of AAs carry a coding variant of the APOL1 gene (G1 APOL1 or G2 APOL1). The disease phenotypes associated with APOL1 risk variants (RV) depend on the cell type-specific expression and toxicity of APOL1. Our recent studies (single-cell, single nuclei, and in-situ hybridization) have shown APOL1 is highly expressed in the endothelial cells of human kidneys. Individuals who carry the G1 or G2 APOL1 RV have a high risk of developing hypertensive kidney disease. However, the direct role of APOL1 in the development of hypertension and hypertensive kidney disease remains unclear.

Methods

Endothelial-specific inducible expression of APOL1 (EC/G0-APOL1, EC/G2-APOL1) mice were generated by using Tet-off system. Upon removal of doxycycline diet, APOL1 expression was obtained in various vascular beds. For the high salt diet model, UNX surgery was performed on WT control, EC/G0-APOL1, and EC/G2-APOL1 mice, followed by a high-salt diet (4%) for 12 weeks post-surgery. We processed snRNA-seq, bulk RNA-seq, and spatial transcriptomics, and combined these with genetic and pharmacologic approaches to investigate the role of G2APOL1 RV in the development of hypertension.

Results

Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) were statically increased in Cdh5tTA/TRE-G2APOL1 mice compared to control WT/G0 mice after 14 weeks of continuous G2APOL1 RV expression in endothelial cells. A high-salt diet following UNX surgery further augments elevated blood pressure and induces renal dysfunction in EC/G2APOL1 mice. Comprehensive in vivo and in vitro investigations revealed that RV APOL1 expressed in endothelial cells triggers the activation of the STING pathway, fostering the production of endothelin-1 (ET-1). STING-specific knockout in endothelial cells of Cdh5tTA/TRE-G2APOL1 mice led to reduced ET-1 production, as well as reductions in SBP, DBP, and MAP post-UNX surgery and high-salt diet.

Conclusion

Endothelial-specific expression of G2APOL1 RV activates the STING pathway, promoting ET-1 production and contributing to hypertension development, subsequently results in renal damage.

Funding

• NIDDK Support