ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: FR-OR02

Estrogen Protects Female Mice With CKD From Developing FGF23-Induced Left Ventricular Hypertrophy

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Kentrup, Dominik, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Courbon, Guillaume, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Wang, Xueyan, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Hunt-Tobey, Bridget, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • David, Valentin, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Martin, Aline, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background

Elevated levels of serum fibroblast growth factor 23 (FGF23) directly contribute to the development of left ventricular hypertrophy (LVH) and mortality in patients with chronic kidney disease (CKD). Although the risk of cardiovascular events and mortality is significantly higher in men than in women, the sex-specific differences in FGF23-induced LVH are unclear.

Methods

We studied age-matched C57BL/6J wild-type (WT) and Col4a3 knockout (CKD) male and female littermate mice with progressive CKD at 4, 8, 12, 16, and 20 weeks of age. We analyzed kidney and heart morphology and function and circulating markers of mineral metabolism in all mice. We performed RNAseq analyses on hearts isolated from 20 week-old mice. We assessed lifespan in a separate set of mice. In vitro, we isolated primary cardiomyocytes (NMCMs) from mouse neonates separated by sex, and cultured them in presence of FGF23, estradiol (E2), both or none.

Results

Compared to WT, CKD males showed elevated blood urea nitrogen (BUN) levels starting at 16 weeks of age indicating onset of CKD. Concomitant with CKD progression, serum levels of FGF23 also started to increase at 16 weeks. At 20 weeks, CKD males showed overt LVH and died at 22 weeks. In contrast, CKD females showed an earlier decline in kidney function and increase in FGF23 levels at 12 weeks of age. At all timepoints, CKD females displayed higher FGF23 levels than CKD males. However, CKD females did not develop LVH and lived until 24 weeks. Heart transcriptomics analyses showed that differentially regulated LVH-related genes were downstream targets of estrogen receptor 1. In culture, E2 alone slightly reduced the size of female NMCMs, but had no effect on male cells. In contrast, FGF23 induced similar hypertrophic growth in male and female NMCMs. E2 co-treatment partially reduced the dose-dependent FGF23 hypertrophic effects in male cells and fully prevented them in female cells.

Conclusion

CKD female mice do not develop LVH and live longer than CKD males, despite an earlier CKD onset and higher FGF23, indicating that the mechanisms leading to LVH in CKD are sex-dependent. This study shows that estradiol cancels the direct hypertrophic effects of FGF23 on female cardiomyocytes, suggesting the presence of common molecular targets of FGF23 and E2 signaling in the heart.

Funding

  • NIDDK Support