The elevation of circulating fibroblast growth factor 23 without kidney disease does not increase cardiovascular disease risk.

Abstract

High circulating fibroblast growth factor 23 (FGF23) levels are probably a major risk factor for cardiovascular disease in chronic kidney disease. FGF23 interacts with the receptor FGFR4 in cardiomyocytes inducing left ventricular hypertrophy. Moreover, in the liver FGF23 via FGFR4 increases the risk of inflammation which is also found in chronic kidney disease. In contrast, X-linked hypophosphatemia is characterized by high FGF23 circulating levels due to loss of function mutations of the phosphate-regulating gene with homologies to an endopeptidase on the X chromosome (PHEX), but is not characterized by high cardiovascular morbidity. Here we used a novel murine X-linked hypophosphatemia model, the PhexC733RMhda mouse line, bearing an amino acid substitution (p.Cys733Arg) to test whether high circulating FGF23 in the absence of renal injury would trigger cardiovascular disease. As X-linked hypophosphatemia patient mimics, these mice show high FGF23 levels, hypophosphatemia, normocalcemia, and low/normal vitamin D levels. Moreover, these mice show hyperparathyroidism and low circulating soluble αKlotho levels. At the age of 27 weeks we found no left ventricular hypertrophy and no alteration of cardiac function as assessed by echocardiography. These mice also showed no activation of the calcineurin/NFAT pathway in heart and liver and no tissue and systemic signs of inflammation. Importantly, blood pressure, glomerular filtration rate and urea clearance were similar between genotypes. Thus, the presence of high circulating FGF23 levels alone in the absence of renal impairment and normal/high phosphate levels is not sufficient to cause cardiovascular disease.

• Authors: Eva-Maria Pastor-Arroyo, Nicole Gehring, Christiane Krudewig, Sarah Costantino, Carla Bettoni, Thomas Knöpfel, Sibylle Sabrautzki, Bettina Lorenz-Depiereux, Johanne Pastor, Tim M Strom, Martin Hrabě de Angelis, Giovanni G Camici, Francesco Paneni, Carsten A Wagner, Isabel Rubio-Aliaga
• Journal: Kidney international (Kidney Int) Vol. 94 Issue 1 Pg. 49-59 (07 2018) ISSN: 1523-1755 [Electronic] United States
• PMID: 29735309 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Chemical References

• FGF23 protein, human
• Fgf23 protein, mouse
• Phosphates
• Fibroblast Growth Factors
• Fibroblast Growth Factor-23
• PHEX Phosphate Regulating Neutral Endopeptidase
• Phex protein, mouse

Topics

• Animals
• Disease Models, Animal
• Echocardiography
• Familial Hypophosphatemic Rickets (blood, genetics)
• Female
• Fibroblast Growth Factor-23
• Fibroblast Growth Factors (blood, metabolism)
• Heart (diagnostic imaging)
• Humans
• Hypertrophy, Left Ventricular (blood, diagnosis, epidemiology, etiology)
• Loss of Function Mutation
• Male
• Mice
• Mice, Transgenic
• PHEX Phosphate Regulating Neutral Endopeptidase (genetics, metabolism)
• Phosphates (blood)
• Renal Insufficiency, Chronic (blood, complications)
• Risk Factors
• X-Ray Microtomography