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Updated: May 1, 2026
An In Vivo Estrogen Deficiency Mouse Model for Screening Exogenous Estrogen Treatments of Cardiovascular Dysfunction After Menopause
Published on: August 13, 2019
Estrogen protects female mice with chronic kidney disease from fibroblast growth factor 23-induced left ventricular
Dominik Kentrup1, Jane Joy Thomas1, Guillaume Courbon1
1Division of Nephrology and Hypertension, Center for Translational Metabolism and Health, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Insights
Estrogen protects female hearts in chronic kidney disease (CKD) by blocking fibroblast growth factor 23 (FGF23)-induced hypertrophy. This highlights sex-specific mechanisms against cardiovascular disease in CKD.
Area of Science:
- Cardiovascular Biology
- Nephrology
- Endocrinology
Background:
- Fibroblast growth factor 23 (FGF23) is linked to left ventricular hypertrophy (LVH) and mortality in chronic kidney disease (CKD).
- Males exhibit a higher cardiovascular event risk than females, with estrogen known to have cardiac protective effects.
- The impact of CKD on cardiac FGF23 signaling in females remains under investigation.
Purpose of the Study:
- To investigate sex-specific differences in cardiac FGF23 signaling during CKD progression.
- To identify molecular targets of FGF23 in CKD-associated LVH.
- To determine the interplay between FGF23, estrogen, and cardiac hypertrophy in CKD.
Main Methods:
- Utilized age-matched wild-type and Col4a3 knockout mice to model CKD, assessing kidney and heart phenotypes.
- Employed transcriptomics to identify FGF23 targets in CKD-induced LVH.
- Examined the effects of FGF23 and estradiol (E2) in vivo and on cultured neonatal mouse cardiomyocytes (NMCMs), with sex-specific analysis.
Main Results:
- CKD males developed LVH and had higher mortality, while CKD females did not develop LVH and lived longer, despite similar FGF23 increases.
- RNA sequencing revealed FGF23 targets in male CKD hearts are downstream of estrogen signaling.
- In vitro, FGF23 induced cardiac hypertrophy in NMCMs, an effect blocked by E2 co-treatment. E2 also prevented FGF23-induced calcineurin activity in male hearts.
Conclusions:
- Identified shared molecular targets for FGF23 and estrogen signaling in the heart.
- Demonstrated that estrogen antagonizes the hypertrophic effects of FGF23.
- Provided evidence for female-specific cardioprotective mechanisms against CKD-associated cardiac remodeling.
Introduction:
Fibroblast growth factor 23 (FGF23) contributes to left ventricular hypertrophy (LVH) and mortality in chronic kidney disease (CKD). Males have a higher risk of cardiovascular events than females. The protective effects of estrogen on the heart are well established, but it remains unclear if cardiac FGF23 signaling is modified in females with CKD.
Methods:
We studied mineral metabolism, kidney and heart phenotypes of age-matched wild-type (WT) and Col4a3 knockout (Col4a3KO) mice during CKD progression and used transcriptomics to identify proximal targets of FGF23 involved in CKD-associated LVH. Additionally, we tested the effects of FGF23 and estradiol (E2) in vivo and on cultured neonatal mouse cardiomyocytes (NMCMs). All results were separated by sex.
Results:
Compared to WT, CKD males showed progressive increases in blood urea nitrogen (BUN) and FGF23 levels, overt LVH at 20 weeks, and premature death at 22 weeks. In contrast, CKD females showed earlier increases in BUN and FGF23 levels but did not develop LVH and lived longer than males. RNA sequencing analyses revealed that the proximal targets of FGF23 identified in males with CKD are established downstream targets of estrogen signaling. In vitro, FGF23 induced the hypertrophic growth of NMCMs isolated from male and female mice and E2 co-treatment prevented this effect. Finally, E2 prevented FGF23-induced calcineurin activity in the heart of male mice, whereas ovariectomy triggered the development of LVH in female mice with CKD.
Conclusions:
We identified common molecular targets of FGF23 and E2 signaling in the heart and show that estrogen antagonizes the hypertrophic effects of FGF23, supporting female-specific cardioprotective mechanisms in CKD.
