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Abstract: SA-OR34

Paracrine FGF-23 Signaling in the Heart Causes Cardiac Hypertrophy

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms

Authors

  • Campos, Isaac D., The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States
  • Richter, Beatrice, The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States
  • Yanucil, Christopher, The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States
  • Czaya, Brian A., The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States
  • Heitman, Kylie, The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States
  • Kentrup, Dominik, The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States
  • Westbrook, David Gibbs, The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States
  • Faul, Christian, The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States
Background

Elevated serum levels of the phosphaturic hormone, fibroblast growth factor (FGF) 23, contribute to cardiac hypertrophy in chronic kidney disease (CKD). FGF23 directly targets cardiac myocytes via FGF receptor (FGFR) 4 to induce hypertrophic growth and FGFR4 blockade not only protects rodent models of CKD from cardiac hypertrophy but also from fibrosis. Our cell culture studies indicate that cardiac fibroblasts do not directly respond to FGF23. It is known that a miscommunication between cardiac myocytes and fibroblasts contributes to pathologic cardiac remodeling. It has been shown that in rodent models and patients with CKD, as well as in mice on high phosphate diet without kidney injury, the heart starts to produce FGF23. Here, we studied if by targeting cardiac myocytes FGF23 promotes paracrine signaling that drives fibrosis. We aimed to determine the cardiac cell type(s) that act as FGF23 source and study if FGF23 serves as a novel paracrine signal mediator between cardiac cell types.

Methods

We treated cultured cardiac myocytes with FGF23 and determined expression levels of established paracrine signal mediators (IL6, LIF, TGFβ, FGF2), or with high phosphate and analyzed FGF23 expression, all by qPCR. We isolated cardiac fibroblasts from wildtype mice on a high phosphate (2%) diet or control chow (0.7%) for 12 weeks. We analyzed paracrine signal mediators by qPCR, as well as FGF23 by qPCR and ELISA. After plating cardiac fibroblasts for 24 and 48 hours, we transferred cell supernatants to myocytes and analyzed hypertrophy.

Results

FGF23 did not increase the expression of paracrine signal mediators in cardiac myocytes or fibroblasts. Phosphate elevations induced FGF23 expression in cardiac fibroblasts, but not in myocytes. Cardiac fibroblast-derived supernatants showed pro-hypertrophic activity when transferred to myocytes, which could be inhibited by co-administration of blocking antibodies for FGF23 or FGFR4.

Conclusion

FGF23 does not affect cardiac fibroblasts by regulating paracrine signal mediators in myocytes. However, FGF23 acts as a novel fibroblast-derived paracrine signaling mediator that induces hypertrophic growth of cardiac myocytes in an FGFR4-dependent manner in scenarios of hyperphosphatemia, such as CKD.

Funding

  • Private Foundation Support