Kidney Week

Abstract: TH-PO219

Apolipoprotein-L1 G1 Variant Contributes to Hydrocephalus but Not to Atherosclerosis

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

• Yoshida, Teruhiko, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States

Teruhiko Yoshida, MD, PhD

• Yang, Zhi-Hong, National Heart Lung and Blood Institute, Bethesda, Maryland, United States

Zhi-Hong Yang, PhD

• Ashida, Shinji, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States

Shinji Ashida, MD, PhD

• Yu, Zu-Xi, National Heart Lung and Blood Institute, Bethesda, Maryland, United States

Zu-Xi Yu, MD, PhD

• Shrivastav, Shashi, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States

Shashi Shrivastav, PhD

• Springer, Danielle A., National Heart Lung and Blood Institute, Bethesda, Maryland, United States

Danielle A. Springer, DVM

• Starost, Matthew, National Institutes of Health Office of the Director, Bethesda, Maryland, United States

Matthew Starost, PhD, DVM

• Rosenberg, Avi Z., Johns Hopkins University, Baltimore, Maryland, United States

Avi Z. Rosenberg, MD, PhD

• Remaley, Alan T., National Heart Lung and Blood Institute, Bethesda, Maryland, United States

Alan T. Remaley, MD, PhD

• Kopp, Jeffrey B., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States

Jeffrey B. Kopp, MD, FASN

Background

In the USA, six million individuals with sub-Saharan ancestry carry two apolipoprotein L1 (APOL1) high-risk genetic variants, which increase risk for kidney diseases. Whether APOL1 high-risk variants are independent risk factors for cardiovascular diseases requires further investigation.

Methods

Transgenic mice carrying APOL1 (G0 low-risk variant and G1 high-risk variant) on bacterial artificial chromosomes (BAC/APOL1 mice) were crossed with the apolipoprotein E knock-out (ApoE-KO) atherosclerosis mouse model. The dual transgenic mice were evaluated for the impact of APOL1 variants on systemic phenotypes. The associations between APOL1 variants and hydrocephalus were analyzed in the NIH All of Us cohort.

Results

ApoE-KO mice carrying APOL1-G0 and APOL1-G1 transgenes did not show differences in the extent of atherosclerotic lesions or aortic calcification, as evaluated by Sudan IV staining and radiographic examination (Figure A-C). All these mice lacked albuminuria. However, ~21% of APOL1-G1 mice developed hydrocephalus and died early (Figure D, E). The hydrocephalus was likely due to excess CSF production by the choroid plexus, where epithelial cells expressed APOL1. Single-nucleus RNA-seq of choroid plexus identified multiple solute transporter upregulation and mTORC2 pathway activation in APOL1-G1-expressing epithelial cells. Further, in the NIH All of Us cohort, there was higher hydrocephalus prevalence among African-Americans with the APOL1-G1 variant, in both recessive (odds ratio 4.35 [1.93-8.88]) and dominant models (3.86 [2.09-7.50]), supporting the mouse findings.

Conclusion

While APOL1-G1 expression in ApoE-KO mice did not worsen cardiovascular or kidney disease, we identified hydrocephalus as a novel APOL1-G1 variant-mediated phenotype. These findings extend the spectrum of APOL1-associated pathologies.

(A) Sudan IV-stained images of whole dissected aorta, (B) quantitative results of aortic plaque area, (C) quantitative results of aortic calcification, (D) Kaplan-Meier survival curve, and (E) domed-head appearance of hydrocephalus in ApoE-KO/APOL1-G1 mice.

Funding

• NIDDK Support