Estrogen protects female mice with chronic kidney disease from fibroblast growth factor 23-induced left ventricular hypertrophy.

Abstract

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. 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. 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. 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.