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Abstract: SA-PO764

Endothelial Cell-Specific G2APOL1 Expression Induces Hypertension via STING and NLRP3 Pathways

Session Information

  • Hypertension and CVD: Mechanisms
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

  • 1503 Hypertension and CVD: Mechanisms

Authors

  • Poudel, Bibek, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Wahba, Joseph, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Vassalotti, Allison, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Raman, Archana, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Wu, Junnan, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Susztak, Katalin, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
Background

Genetic studies showed an association between ApolipoproteinL1 (APOL1) high risk (G1/G2) genotype and hypertension (HTN) and hypertensive kidney disease (H-CKD). The causal role of APOL1 in the development of HTN and H-CKD is not fully understood.

Methods

In the human kidney, APOL1 is highly expressed in endothelial cells and podocytes. We generated endothelial and podocyte-specific inducible G0 and G2 APOL1 transgenic mice by crossing the TRE-G2APOL1 and TRE-G0-APOL1 mice with the endothelial-specific Cdh5tTA and podocyte-specific (NPHS1rtTA) transgenic mice. We induced APOL1 expression by doxycycline diet. In the Cdh5tTA/TRE-G2APOL1 and control mice, we performed uni-nephrectomy (UNX) at five weeks of age and kept mice on a 4% salt diet for 12 weeks. Blood pressure was monitored by the tail-cuff method. To understand the role of the inflammasome (NLRP3 and GSDMD) and the cytosolic nucleotide sensor (STING) in disease development, we crossed the STING, NLRP3, and GSDMD knock-out mice with the Cdh5tTA/TRE-G2APOL1 animals.

Results

Podocyte-specific G2APOL1 transgenic mice developed severe HTN only after proteinuria and renal damage was observed, likely representing a secondary HTN. Systolic, diastolic, and mean arterial blood pressure was mildly but significantly higher in Cdh5tTA/TRE-G2APOL1 mice compared to control mice. Cdh5tTA/TRE-G2APOL1 mice also developed a slight increase in urinary albumin/creatinine ratio and renal fibrosis after the animals became hypertensive. Hypertension, renal fibrosis, and proteinuria were ameliorated in STING, NLRP3, and GSDMD knock-out Cdh5tTA/TRE-G2APOL1 mice compared to Cdh5tTA/TRE-G2APOL1 mice. Our preliminary data indicate an increased cytosolic leakage of mitochondrial DNA in Cdh5tTA/TRE-G2APOL1 mice, which is likely responsible for the STING, NLRP3, and GSDMD activation in the Cdh5tTA/TRE-G2APOL1 mice.

Conclusion

EC-specific G2APOL1 transgenic mice developed mild salt-sensitive hypertension and renal damage, indicating the causal role of G2APOL1 in hypertension and hypertensive kidney disease, while podocyte-specific G2APOL1 was associated with secondary hypertension. This project was supported by DK105821.

Funding

  • NIDDK Support