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Abstract: FR-OR073

Different Outcome of Cardiac Remodeling in Two Mouse Models with FGF23 Excess and Klotho Deficiency

Session Information

Category: Mineral Disease

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

Authors

  • Richter, Beatrice, Hannover Medical School, Hannover, Germany
  • Basaran, Melis, Hannover Medical School, Hannover, Germany
  • Alesutan, Ioana, Charité University Medicine, Berlin, Germany
  • Voelkl, Jakob, Charité University Medicine, Berlin, Germany
  • Lang, Florian C., University of Tuebingen, Tuebingen, Germany
  • Haffner, Dieter, Hannover Medical School, Hannover, Germany
  • Leifheit-Nestler, Maren, Hannover Medical School, Hannover, Germany
Background

High levels of fibroblast growth factor-23 (FGF23), phosphate and parathyroid hormone (PTH) as well as deficiency in active vitamin D (1,25D) and klotho are strongly associated with the development of cardiovascular disease, including left ventricular hypertrophy and myocardial fibrosis. In vivo, klotho and 1,25D improve cardiac hypertrophy and in vitro, klotho inhibits fibroblast activation and collagen synthesis in the heart and protects against FGF23-induced oxidative stress.

Methods

Heart tissue from two mouse models with high FGF23 serum levels and klotho deficiency was analyzed: 1) klotho hypomorphic (KL-/-) mice displaying both high phosphate and 1,25D levels, but low PTH; 2) Hyp mouse presenting high PTH, but low plasma levels of phosphate and 1,25D.

Results

For both mouse models an enhanced relative heart weight and raised cross-sectional area of cardiomyocytes were detected when compared to respective wild type controls. In KL-/- mice, a clear increase of cardiac Fgf23, Fgfr4, activation of calcineurin/NFAT signaling and induction of pro-hypertrophic genes Rcan1, BNP, ANP and bMHC was seen. Furthermore, KL-/- mice showed an enhanced expression of transcription factors (Cebpb, Gata4) and fibrosis-related factors (Tgfb1, collagen 1, Mmp2) that are involved in cardiac remodeling events. In contrast, Hyp mice presented a strong increase of cardiac Fgf23 mRNA and intact cardiac Fgf23 protein as well, but missed the induction of the Fgfr4/calcineurin/NFAT pathway. Moreover, the expression of the pro-hypertrophic markers BNP, ANP, bMHC and pro-fibrotic factors was absent in Hyp mice.

Conclusion

Despite the FGF23 excess, high PTH, low 1,25D and reduced klotho, it seems that Hyp mice are protected from the development of pathological heart changes may be due to hypophosphatemia. Contrary, KL-/- mice show induced cardiac hypertrophy and fibrosis though high 1,25D plasma levels.