Abstract: FR-OR072

Cardiac Hypertrophy Elevates Serum FGF23

Session Information

Category: Mineral Disease

  • 1202 Mineral Disease: Vitamin D, PTH, FGF-23

Authors

  • Shimada, Karin, Osaka University Graduate School of Medicine, Suita, Japan
  • Sakaguchi, Yusuke, Osaka University Graduate School of Medicine, Suita, Japan
  • Hamano, Takayuki, Osaka University Graduate School of Medicine, Suita, Japan
  • Isaka, Yoshitaka, Osaka University Graduate School of Medicine, Suita, Japan
  • Matsui, Isao, Osaka University Graduate School of Medicine, Suita, Japan
  • Oka, Tatsufumi, Osaka University Graduate School of Medicine, Suita, Japan
  • Mori, Daisuke, Osaka University Graduate School of Medicine, Suita, Japan
  • Hashimoto, Nobuhiro, Osaka University Graduate School of Medicine, Suita, Japan
  • Matsumoto, Ayumi, Osaka University Graduate School of Medicine, Suita, Japan
  • Yamaguchi, Satoshi, Osaka University Graduate School of Medicine, Suita, Japan
  • Kubota, Keiichi, Osaka University Graduate School of Medicine, Suita, Japan
  • Yonemoto, Sayoko, Osaka University Graduate School of Medicine, Suita, Japan
Background


FGF23 is a potent phosphaturic hormone predominantly produced by the bone. Although several studies have revealed FGF23 induces left ventricular hypertrophy (LVH), effect of LVH on FGF23 remains uncertain.

Methods


The activation of calcineurin/NFAT pathway plays pivotal roles in the development of pathological LVH. Therefore, we performed experiments using cardiomyocyte-specific calcineurin A transgenic (TG) mice.

Results

The TG mice at 6-week-old showed severe LVH. Body weight, systolic blood pressure, food intake, water intake, urinary volume, and creatinine clearance were not different between wild type (WT) and the TG mice. We found that serum intact FGF23 (iFGF23) in the TG mice were elevated (TG 125.6 ± 16.1 vs. WT 87.5 ± 10.1 pg/mL, P=0.0107). Both real time PCR and immunohistochemistry revealed that the elevation of iFGF23 in the TG mice was derived from hypertrophic cardiomyocytes but not from the bone. The promoter region of the FGF23 gene contained two putative NFAT-biding sites. Luciferase assay showed that NFAT1 activates the promoter in a proximal NFAT-binding site dependent manner. Although serum level of iFGF23 was elevated in the TG mice, all parameters — serum, urinary, and fractional excretion of calcium/phosphate, and serum 1,25(OH)2 vitamin D — were not different between the WT and the TG mice. Renal levels of α-klotho were also at comparable levels between the two groups. We found that plasma ADH levels of the TG mice were higher than those of the WT mice (TG 1.01 ± 0.68 vs. WT 0.40 ± 0.46 pg/mL, P=0.0306). To investigate the effects of ADH on the function of FGF23, we injected ADH and/or FGF23 into WT mice. As previously reported, FGF23 suppressed renal mRNA levels of CYP27B1. The suppression of CYP27B1 was restored by ADH. In addition, FGF23-dependent elevation of CYP24 was suppressed by ADH. Both FGF23 and ADH did not affect expression levels of α-klotho in the kidney.

Conclusion


Hypertrophic cardiomyocyte produces FGF23. Proximal NFAT-binding site in the FGF23 gene promoter was important for the transcriptional regulation of FGF23. ADH causes FGF23-resistance in the kidney.

Funding

  • Private Foundation Support