Abstract: TH-PO754
Preeclamptic Phenotype in Transgenic Mice With Fetuses Carrying APOL1 Risk Variants
Session Information
- Sex and Reproductive Factors in Kidney Health
November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Women's Health and Kidney Diseases
- 2100 Women's Health and Kidney Diseases
Authors
- Yoshida, Teruhiko, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
- Latt, Khun Zaw, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
- Lu, Huiyan, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
- Reidy, Kimberly J., Children's Hospital at Montefiore, Bronx, New York, United States
- Charlton, Jennifer R., University of Virginia, Charlottesville, Virginia, United States
- Zhao, Yongmei, Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States
- Shrivastav, Shashi, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
- Reznik, Sandra E., Children's Hospital at Montefiore, Bronx, New York, United States
- Rosenberg, Avi Z., Johns Hopkins University, Baltimore, Maryland, United States
- Winkler, Cheryl Ann, Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States
- Kopp, Jeffrey B., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
Background
African Americans experience more pregnancy complications, including preeclampsia, compared to others. African-origin genetic variants in apolipoprotein L1 (APOL1), promote various renal disorders. Recent clinical studies showed that fetuses with two APOL1 risk variants predispose the mother to preeclampsia. The mechanisms of APOL1-asociated preeclampsia remain poorly understood. Here we made use of a transgenic mouse model to investigate these mechanisms.
Methods
We in-vitro-fertilized CD-1 female mice using sperm from human APOL1 gene locus transgenic mice carrying a bacterial artificial chromosome bearing either the APOL1-G0 allele (common variant) or the APOL1-G1 allele (risk variant). We measured systolic blood pressure with a tail cuff. We euthanized mice at E18.5 and collected fetuses, placenta and maternal plasma. We evaluated the phenotype of the dam by plasma chemistry and assessed weight of fetuses and placenta. We characterized placental transcriptomic profiles by single-nuclear RNA-seq.
Results
Compared with a dam with APOL1-G0 fetuses, a dam with APOL1-G1 fetuses had higher systolic blood pressure, 158 [141-163] vs 116 [115-131] mmHg; median [IQR], P=0.01) and had lower plasma placental growth factor-2 levels (32 [20-82] vs 126 [98-260] pg/mL; P=0.047). APOL1-G1 fetuses had lower relative weights, (0.95 [0.90-0.98] vs 1.0 [0.96-1.04]; P=0.03) when compared with WT fetuses. By contrast, APOL1-G0 fetuses had relative weights similar to wild-type (WT) fetuses (0.99 [0.95-1.08]; P=1.0). Single-nucleus RNA-seq demonstrated increased expression of inflammation-related genes (e.g. Spp1, encoding osteopontin; Lyz2, encoding lysozyme2) in APOL1-expressing endothelial cells and trophoblasts in placentas of APOL1-G1 fetuses compared with placentas of APOL1-G0 and WT fetuses.
Conclusion
This APOL1 mouse preeclampsia model suggests that the APOL1-G1 allele promotes endothelial and trophoblastic inflammation and thus contributes to placental dysfunction and preeclamptic phenotypes, similar to human disease.
Funding
- NIDDK Support