Vitamin D treatment attenuates cardiac FGF23/FGFR4 signaling and hypertrophy in uremic rats.
BACKGROUND
Vitamin D deficiency and excess of circulating fibroblast growth factor 23 (FGF23) contribute to cardiovascular mortality in patients with chronic kidney disease (CKD). FGF23 activates FGF receptor 4 and (FGFR4) calcineurin/nuclear factor of activated T cells (NFAT) signaling in cardiac myocytes, thereby causing left ventricular hypertrophy (LVH). Here, we determined if 1,25-dihydroxyvitamin D (calcitriol) inhibits FGF23-induced cardiac signaling and LVH.


METHODS
5/6 nephrectomized (5/6 Nx) rats were treated with different doses of calcitriol for 4 or 10 weeks and cardiac expression of FGF23/FGFR4 and activation of calcineurin/NFAT as well as LVH were analyzed. FGFR4 activation and hypertrophic cell growth were studied in cultured cardiac myocytes that were co-treated with FGF23 and calcitriol.


RESULTS
In 5/6Nx rats with LVH, we detected elevated FGF23 expression in bone and myocardium, increased cardiac expression of FGFR4 and elevated cardiac activation of calcineurin/NFAT signaling. Cardiac expression levels of FGF23 and FGFR4 significantly correlated with the presence of LVH in uremic rats. Treatment with calcitriol reduced LVH as well as cardiac FGFR4 expression and calcineurin/NFAT activation. Bone and cardiac FGF23 expression were further stimulated by calcitriol in a dose-dependent manner, but levels of intact cardiac FGF23 protein were suppressed by high-dose calcitriol. In cultured cardiac myocytes, co-treatment with calcitriol blocked FGF23-induced activation of FGFR4 and hypertrophic cell growth.


CONCLUSIONS
Our data suggest that in CKD, cardioprotective effects of calcitriol stem from its inhibitory actions on the cardiac FGF23/FGFR4 system, and based on their counterbalancing effects on cardiac myocytes, high FGF23 and low calcitriol synergistically contribute to cardiac hypertrophy.
Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
Maren
M
Leifheit-Nestler
Department of Medicine, Katz Family Drug Discovery Center and Division of Nephrology and Hypertension, University of Miami Miller School of Medicine, Miami, FL, USA.
Alexander
A
Grabner
Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
Laura
L
Hermann
Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
Beatrice
B
Richter
Department of Pediatrics, University Hospital Rostock, Rostock, Germany.
Karin
K
Schmitz
Department of Pediatrics, University Hospital Rostock, Rostock, Germany.
Dagmar-Christiane
DC
Fischer
Department of Medicine, Katz Family Drug Discovery Center and Division of Nephrology and Hypertension, University of Miami Miller School of Medicine, Miami, FL, USA.|Department of Cell Biology and Anatomy, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA.
Christopher
C
Yanucil
Department of Medicine, Katz Family Drug Discovery Center and Division of Nephrology and Hypertension, University of Miami Miller School of Medicine, Miami, FL, USA.|Department of Cell Biology and Anatomy, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA.
Christian
C
Faul
Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
Dieter
D
Haffner
D000818:Animals; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000150:complications*; D015398:Signal Transduction; D014807:Vitamin D / Q000008:administration & dosage*; D014815:Vitamins / Q000008:administration & dosage
C000717427:FGF23 protein, human; C505605:Fgf23 protein, rat; D014815:Vitamins; D014807:Vitamin D; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; C496373:Fgfr4 protein, rat; D051499:Receptor, Fibroblast Growth Factor, Type 4
cardiac hypertrophy; chronic kidney disease; fibroblast growth factor 23; fibroblast growth factor receptor 4; vitamin D