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Abstract: TH-PO513

FGF23-Mediated Activation of RAAS Contributes to Cardiac Hypertrophy and Fibrosis

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Leifheit-Nestler, Maren, Hannover Medical School, Hannover, Germany
  • Boeckmann, Ineke, Hannover Medical School, Hannover, Germany
  • Lischka, Jonas, Hannover Medical School, Hannover, Germany
  • Richter, Beatrice, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Deppe, Jennifer, Hannover Medical School, Hannover, Germany
  • Haffner, Dieter, Hannover Medical School, Hannover, Germany
Background

Patients with CKD develop LVH accompanied with LV fibrosis. One of the main causes are the increased FGF23 serum levels, which were shown to induce the calcineurin/NFAT pathway in cardiomyocytes. Additionally, CKD patients show a systemic activation of RAAS and FGF23 is discussed to stimulate RAAS activation, which could be an alternative mechanism for the progression of FGF23-mediated cardiac pathologies. However, underlying molecular mechanisms are unknown.

Methods

We evaluated LVH and fibrosis in association with cardiac FGF23 and the local activation of RAAS in heart tissue of 5/6 nephrectomized (5/6Nx) rats compared to sham-operated animals. In order to distinguish between FGF23-mediated LVH and fibrosis via calcineurin/NFAT or RAAS, we stimulated isolated neonatal rat ventricular myocytes (NRVM) and fibroblast (NRCF) with FGF23 in the presence and absence of cyclosporine A, losartan and spironolactone, and investigated hypertrophic and fibrotic pathways by qPCR, Western blot and functional analysis.

Results

Uremic rats showed increased relative heart weight accompanied with enhanced cardiomyocyte size and LV fibrosis compared with sham. The cardiac expression of Fgf23 and RAAS genes were significantly increased in 5/6Nx rats and correlated with the degree of LV fibrosis.
FGF23 stimulated the expression of RAAS genes in cardiac cells in vitro and induced NGAL indicating mineralocorticoid receptor activation. The FGF23-induced hypertrophic growth of NRVM was attenuated by pre-treatment with cyclosporine A, losartan and spironolactone. In addition, the FGF23-mediated induction of pro-hypertrophic NFAT target genes was blocked by inhibition of calcineurin, AT1R and mineralocorticoid receptor. In NRCF, FGF23 phosphorylated Smad2/3 and induced Tgf-b and Ctgf, which were only suppressed by pre-stimulation with losartan and spironolactone but not with cyclosporine A. Interestingly, FGF23 increased the proliferation of NRCF independent of calcineurin/NFAT and RAAS activation.

Conclusion

The FGF23-induced cardiac hypertrophy is mediated by both the activation of RAAS and calcineurin/NFAT. Moreover, FGF23 impact on cardiac fibrosis primarily via RAAS-mediated activation of Tgf-b/Smad pathway.