Increased FGF23 protects against detrimental cardio-renal consequences during elevated blood phosphate in CKD
Erica L. Clinkenbeard, … , Matthew R. Allen, Kenneth E. White
Erica L. Clinkenbeard, … , Matthew R. Allen, Kenneth E. White
Published February 21, 2019
Citation Information: JCI Insight. 2019;4(4):e123817. https://doi.org/10.1172/jci.insight.123817.
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Research Article Endocrinology Genetics

Increased FGF23 protects against detrimental cardio-renal consequences during elevated blood phosphate in CKD

Abstract

The phosphaturic hormone FGF23 is elevated in chronic kidney disease (CKD). The risk of premature death is substantially higher in the CKD patient population, with cardiovascular disease (CVD) as the leading mortality cause at all stages of CKD. Elevated FGF23 in CKD has been associated with increased odds for all-cause mortality; however, whether FGF23 is associated with positive adaptation in CKD is unknown. To test the role of FGF23 in CKD phenotypes, a late osteoblast/osteocyte conditional flox-Fgf23 mouse (Fgf23fl/fl/Dmp1-Cre+/–) was placed on an adenine-containing diet to induce CKD. Serum analysis showed casein-fed Cre+ mice had significantly higher serum phosphate and blood urea nitrogen (BUN) versus casein diet and Cre– genotype controls. Adenine significantly induced serum intact FGF23 in the Cre– mice over casein-fed mice, whereas Cre+ mice on adenine had 90% reduction in serum intact FGF23 and C-terminal FGF23 as well as bone Fgf23 mRNA. Parathyroid hormone was significantly elevated in mice fed adenine diet regardless of genotype, which significantly enhanced midshaft cortical porosity. Echocardiographs of the adenine-fed Cre+ hearts revealed profound aortic calcification and cardiac hypertrophy versus diet and genotype controls. Thus, these studies demonstrate that increased bone FGF23, although associated with poor outcomes in CKD, is necessary to protect against the cardio-renal consequences of elevated tissue phosphate.

Authors

Erica L. Clinkenbeard, Megan L. Noonan, Joseph C. Thomas, Pu Ni, Julia M. Hum, Mohammad Aref, Elizabeth A. Swallow, Sharon M. Moe, Matthew R. Allen, Kenneth E. White

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Figure 3

Cardiac phenotypes with clamped FGF23.

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Cardiac phenotypes with clamped FGF23. (A) Echocardiograph images were c...
(A) Echocardiograph images were collected from the mice prior to the 8-week time point. Representative long-axis images collected in B-mode show the aorta (right) down to the apex of the open left ventricle (left). While no gross changes were observed between the genotypes at baseline, the flox-Fgf23/Dmp1-Cre+ mice fed adenine showed thickened aortic walls due to calcification (yellow arrow). Quantification of the aortic diameter in the lower panel demonstrated significantly lower values in the adenine-fed Cre+ mice. Yellow asterisks indicate the apex of the heart; white arrows indicate the aorta to denote similar orientation for each image. (B) Representative H&E staining of casein- and adenine-fed hearts demonstrates pronounced hypertrophy of the left ventricle in the flox-Fgf23/Dmp1-Cre+ mice fed adenine compared with the flox-Fgf23/Dmp1-Cre– mice. Lower panel: Whereas no differences were observed between genotypes on the casein diet, left ventricle wall thickness was higher in the adenine-fed flox-Fgf23/Dmp1-Cre+ mice compared with both casein-fed mice and adenine-fed flox-Fgf23/Dmp1-Cre– mice (n = 4–6 per group). **P < 0.01 versus casein diet within the same genotype; ‡‡P < 0.01 versus flox-Fgf23/Dmp1-Cre– on the same diet. (C) Wheat germ agglutinin staining of the cardiomyocytes demonstrated an increase in cell area, a marker of hypertrophy, in the adenine-fed flox-Fgf23/Dmp1-Cre– mice (lower panel). In the flox-Fgf23/Dmp1-Cre+ adenine-fed group, cell area was significantly increased compared with both casein controls as well as the adenine-fed flox-Fgf23/Dmp1-Cre– mice (n = 30–40 images per group). **P < 0.01 versus casein diet within the same genotype; ‡‡P < 0.01 versus Cre– on the same diet.