Abstract: FR-PO267

Cardiac Fibroblast Growth Factor 23 Is Induced by Activated Renin-Angiotensin-Aldosterone System and Promotes the Pro-Fibrotic Crosstalk between Cardiac Myocytes and Fibroblasts

Session Information

Category: Mineral Disease

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

Authors

  • Leifheit-Nestler, Maren, Hannover Medical School, Hannover, Germany
  • Kirchhoff, Felix, Hannover Medical School, Hannover, Germany
  • Nespor, Julia, Hannover Medical School, Hannover, Germany
  • Richter, Beatrice, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Heineke, Joerg, Hannover Medical School, Hannover, Germany
  • Haffner, Dieter, Hannover Medical School, Hannover, Germany
Background

FGF23 is discussed as a new biomarker associated with cardiac hypertrophy and mortality in patients with CKD, heart failure, and cardiogenic shock. We previously demonstrated that FGF23 is expressed by cardiac myocytes, enhanced in CKD, and induces cardiac hypertrophy via FGFR4-dependent activation of PLCγ/calcineurin/NFAT signaling independent of its co-receptor klotho. However, the impact of FGF23 on cardiac fibrosis is largely elusive.

Methods

By conducting a retrospective case-control study including myocardial autopsy samples from 24 patients with end-stage CKD and in vitro studies in cardiac fibroblasts and myocytes, we investigated the pro-fibrotic properties of FGF23.

Results

The accumulation of fibrillar collagens I and III was increased in myocardial tissue of CKD patients, and correlated with duration of dialysis, PTH, klotho deficiency, and enhanced angiotensinogen (AGT) expression. Using human fibrosis profiler PCR array analyzes, TGF-β and its related TGF-β receptor/Smad complexes, extracellular matrix remodeling enzymes, as well as pro-fibrotic growth factors were significantly upregulated in myocardial tissue of dialysis patients. In cultured cardiac fibroblasts, FGF23 stimulated pro-fibrotic TGF-β receptor/Smad complexes and collagen synthesis, whereas treatment of isolated cardiac myocytes with FGF23 resulted in enhanced collagen remodeling, expression of pro-inflammatory genes, pro-survival pathways, and induction of pro-hypertrophic genes. FGF23 enhanced the expression of Agt in cardiac fibroblasts and myocytes, and angiotensin II and aldosterone, as components of the renin-angiotensin-aldosterone system (RAAS), strongly induced FGF23 in cardiac myocytes to directly promote fibrotic and hypertrophic response.

Conclusion

In conclusion, stimulation with active RAAS components induces FGF23 expression in cardiac myocytes, which in turn stimulates the pro-fibrotic crosstalk between cardiac myocytes and fibroblasts.