FGF23 Induces Left Ventricular Hypertrophy

J Clin Invest. 2011 Nov;121(11):4393-408. doi: 10.1172/JCI46122. Epub 2011 Oct 10.

Abstract

Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor-dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF-receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Animals
  • Cohort Studies
  • Disease Models, Animal
  • Female
  • Fibroblast Growth Factor 2 / administration & dosage
  • Fibroblast Growth Factor 2 / physiology
  • Fibroblast Growth Factors / administration & dosage
  • Fibroblast Growth Factors / physiology*
  • Glucuronidase / deficiency
  • Glucuronidase / genetics
  • Glucuronidase / physiology
  • Humans
  • Hypertrophy, Left Ventricular / etiology*
  • Hypertrophy, Left Ventricular / pathology
  • Hypertrophy, Left Ventricular / physiopathology
  • Kidney Failure, Chronic / complications
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Models, Cardiovascular
  • Myocytes, Cardiac / pathology
  • Myocytes, Cardiac / physiology
  • Prospective Studies
  • Rats
  • Receptors, Fibroblast Growth Factor / physiology
  • Recombinant Proteins / administration & dosage
  • Signal Transduction
  • Young Adult

Substances

  • Fgf23 protein, rat
  • Receptors, Fibroblast Growth Factor
  • Recombinant Proteins
  • Fibroblast Growth Factor 2
  • Fibroblast Growth Factors
  • fibroblast growth factor 23
  • Glucuronidase
  • klotho protein

Grant support