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FGF23 induces left ventricular hypertrophy

Christian Faul1, Ansel P Amaral, Behzad Oskouei

  • 1Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA. cfaul@med.miami.edu

The Journal of Clinical Investigation
|October 12, 2011
PubMed

Insights

Fibroblast growth factor 23 (FGF23) directly causes left ventricular hypertrophy (LVH) in chronic kidney disease (CKD). This FGF23-driven LVH occurs independently of klotho, suggesting new therapeutic targets for cardiovascular disease in CKD patients.

Area of Science:

  • Nephrology
  • Cardiology
  • Endocrinology

Background:

  • Chronic kidney disease (CKD) is a major public health issue linked to increased cardiovascular disease (CVD) mortality.
  • Left ventricular hypertrophy (LVH) is a key mechanism of CVD in CKD patients.
  • Elevated fibroblast growth factor 23 (FGF23) is associated with higher risks of LVH and mortality in CKD, but causality is unclear.

Purpose of the Study:

  • To investigate the causal role of FGF23 in the pathogenesis of LVH in CKD.
  • To explore the FGF23 signaling pathway in cardiac hypertrophy.
  • To determine if FGF23's effect on LVH is dependent on its coreceptor, klotho.

Main Methods:

  • Analysis of FGF23 levels and LVH in a diverse CKD cohort.
  • In vitro studies using isolated rat cardiomyocytes to assess FGF23 effects on hypertrophy via FGF receptor and calcineurin-NFAT pathways.
  • In vivo studies in wild-type and klotho-deficient mice involving FGF23 administration and FGF-receptor blocker treatment in a CKD model.

Main Results:

  • Elevated FGF23 levels were independently associated with LVH in CKD patients.
  • FGF23 induced pathological hypertrophy in rat cardiomyocytes through FGF receptor-dependent calcineurin-NFAT signaling, independent of klotho.
  • FGF23 administration caused LVH in mice; klotho-deficient mice exhibited elevated FGF23 and LVH.
  • FGF-receptor blockade attenuated LVH in a CKD animal model without affecting blood pressure.

Conclusions:

  • FGF23 plays a direct, klotho-independent causal role in the development of LVH in CKD.
  • Chronically elevated FGF23 contributes significantly to LVH and mortality rates in CKD patients.
  • Targeting the FGF23-FGF receptor pathway may offer a novel therapeutic strategy for mitigating cardiovascular risk in CKD.

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