Preeclampsia in mice carrying fetuses with APOL1 risk variants

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African-American women have a maternal mortality rate approximately three times higher than European-American women. This is partially due to hypertensive disorders of pregnancy, including preeclampsia. Fetal APOL1 high-risk genotype increases preeclampsia risk, although mechanisms remain elusive. We characterized two mouse models to investigate whether fetal-origin APOL1 induces preeclampsia and which cell types contribute. We in vitro fertilized mice with sperm from two transgenic mouse lines: APOL1 transgenic mice carrying human genomic locus constructs from bacterial artificial chromosomes (BAC) containing the APOL1 gene, mimicking expression and function of human APOL1 (BAC/APOL1 mice) and albumin promoter APOL1 transgenic mice expressing APOL1 in liver and plasma (Alb/APOL1 mice). Dams carrying either BAC/APOL1-G1 or Alb/APOL1-G1 fetuses had elevated systolic blood pressure, while dams carrying BAC/APOL1-G0 or Alb/APOL1-G0 fetuses did not. BAC/APOL1-G1 and Alb/APOL1-G1 fetuses weighed less than littermates, indicating intrauterine growth restriction. Single-nucleus RNA-seq of APOL1-G1 placentas showed increased expression of osteopontin/Spp1, most prominently in vascular endothelial cells with robust APOL1 expression. Cell-cell interaction analysis indicated pro-inflammatory signaling between placental cells and maternal monocytes. These models show that fetal origin APOL1-G1 causes preeclampsia, inducing pro-inflammatory response in placenta and maternal monocytes. The APOL1-G1 variant poses a multi-generational problem, causing effects in mothers and offspring.

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  1. It is also worth noting thatAlb/APOL1-G1 model showed similar level of phenotypes compared with BAC/APOL1-G1model, except for change in the of sFlt-1/PlGF-2 ratio

    Considering the importance of using the sFlt-1/PIGF ratio as a marker for preeclampsia (the only FDA-approved immunoassay to assess preeclampsia risk is based on the sFlt-1/PIGF ratio), do you believe the BAC/APOL-G1 model is a better model for preeclampsia?

    Given the results of your work, is there a reason where one would prefer to use the Alb/APOL-G1 model?

  2. Dams carrying offspring with BAC/APOL1-G1 andAlb/APOL1-G1 had higher systolic blood pressure (158.4 mmHg [141.3-163.4], P=0.005 and159.0 [137.3-164.8], P=0.0002), compared to dams carrying BAC/APOL1-G0 and Alb/APOL1-G0 mice did not (115.9 [114.5-130.8] and 109.5 [96.3-133.3]) (Figure 1B).

    This sentence is a bit confusing. I’d re-word this to “Dams carrying offspring with BAC/APOL1-G1 and Alb/APOL1-G1 had higher systolic blood pressure (158.4 mm Hg [141.3-163.4], P=0.005 and 159.0 [137.3-164.8], P=0.002) compared to dams carrying BAC/APOL1-G0 and Alb/APOL1-G0 mice (115.9 [114.5-130.8] and 109.5 [96.3-133.3]) (Figure 1B).

  3. The first set of transgenic mice (BAC/APOL1 mice) contained human genomicconstructs from bacterial artificial chromosomes (BAC) containing APOL1-G0 or APOL1-G1.The second set of transgenic mice (Alb/APOL1 mice) had the mouse albumin promotorregulated expression of cDNAs encoding human APOL-G0 or APOL1-G1.

    You mention this later in the discussion but I would include a sentence conveying why you didn’t test APOL1-G2 variants since your introduction refers to both APOL1 high-risk variants (G1 and G2) and to evidence of preeclampsia development in APOL1-G2 transgenic mice (citation 16). E.g. “We did not study APOL1-G2 variants because we did not observe physical preeclampsia phenotypes in these transgenic lines.”

  4. In an attempt to better understand the cell types and molecular mechanisms implicated in preeclampsia, Yoshida et al. analyzed pregnant female mice carrying BAC/APOL-G1 and Alb/APOL-G1 fetuses – novel IVF-derived preeclampsia mouse models – for physical biomarkers of preeclampsia and performed single-nucleus RNA-seq to identify differentially expressed genes and impacted cell-cell interactions.

    When testing physical biomarkers of preeclampsia, the authors found that female mice carrying BAC/APOL-G1 and Alb/APOL-G1 fetuses had higher systolic blood pressure and smaller body weight, while just the female mice carrying BAC/APOL-G1 fetuses had a higher sFlt-1/PIGF-2 ratio. Elevated blood pressure and sFlt-1 levels and lower PIGF levels are phenotypes/markers clinically associated with preeclampsia.

    Single-nucleus RNA-sequencing of placenta was conducted and differentially expressed genes were identified between APOL1-G1 and APOL1-G0 or APOL1-G1 and wild type mice. Inflammatory pathways and autoimmune disease pathways that were identified when comparing human preeclampsia RNA-seq data and a normal control were also implicated in the BAC/APOL1-G1 vs. BAC/APOL1-G0 DEG analysis results (e.g. pathogen induced cytokine storm signaling pathway and HIFI⍺ pathway).

    The authors then performed cell-cell interaction analyses (Seurat) and found 31 shared activated and 4 shared deactivated pathways in BAC/APOL1-G1 placentas compared to BAC/APOL-G0 and wild type placentas. One of the identified shared activated pathways was the osteopontin/Spp1 signaling pathway which was found to be most upregulated in vascular endothelia – the cell type with the highest APOL1 expression.

    Lastly, the authors attempted to determine the impact of maternal monocytes and decidual cells by APOL-G1 placentas and found upregulated signals to monocytes associated with the Cd44 receptor and upregulated expression of Ccl2 – supporting their hypothesis that APOL1-G1 induced preeclampsia in female mice activates maternal monocytes.