TY - JOUR
T1 - Induction of cardiac FGF23/FGFR4 expression is associated with left ventricular hypertrophy in patients with chronic kidney disease
AU - Leifheit-Nestler, Maren
AU - Siemer, Robert Große
AU - Flasbart, Kathrin
AU - Richter, Beatrice
AU - Kirchhoff, Felix
AU - Ziegler, Wolfgang H.
AU - Klintschar, Michael
AU - Becker, Jan U.
AU - Erbersdobler, Andreas
AU - Aufricht, Christoph
AU - Seeman, Tomas
AU - Fischer, Dagmar Christiane
AU - Faul, Christian H
AU - Haffner, Dieter
PY - 2016
Y1 - 2016
N2 - Background: In chronic kidney disease (CKD), serum concentrations of fibroblast growth factor 23 (FGF23) increase progressively as glomerular filtration rate declines, while renal expression of the FGF23 coreceptor Klotho decreases. Elevated circulating FGF23 levels are strongly associated with mortality and with left ventricular hypertrophy (LVH), which is a major cause of cardiovascular death in CKD patients. The cardiac FGF23/FGF receptor (FGFR) system and its role in the development of LVH in humans have not been addressed previously. Methods: We conducted a retrospective case-control study in 24 deceased patients with childhood-onset end-stage renal disease (dialysis: n = 17; transplanted: n = 7), and 24 age- and sexmatched control subjects. Myocardial autopsy samples of the left ventricle were evaluated for expression of endogenous FGF23, FGFR isoforms, Klotho, calcineurin and nuclear factor of activated T-cells (NFAT) by immunohistochemistry, immunofluorescencemicroscopy, qRT-PCR and western blotting. Results: The majority of patients presented with LVH (67%). Human cardiomyocytes express full-length FGF23, and cardiac FGF23 is excessively high in patients with CKD. Enhanced myocardial expression of FGF23 in concert with Klotho deficiency strongly correlates with the presence of LVH. Cardiac FGF23 levels associate with time-averaged serum phosphate levels, up-regulation of FGFR4 and activation of the calcineurin-NFAT signaling pathway, an established mediator of cardiac remodelling and LVH. These changes are detected in patients on dialysis but not in those with a functioning kidney transplant. Conclusions: Our results indicate a strong association between LVH and enhanced expression levels of FGF23, FGFR4 and calcineurin, activation of NFAT and reduced levels of soluble Klotho in the myocardium of patients with CKD. These alterations are not observed in kidney transplant patients.
AB - Background: In chronic kidney disease (CKD), serum concentrations of fibroblast growth factor 23 (FGF23) increase progressively as glomerular filtration rate declines, while renal expression of the FGF23 coreceptor Klotho decreases. Elevated circulating FGF23 levels are strongly associated with mortality and with left ventricular hypertrophy (LVH), which is a major cause of cardiovascular death in CKD patients. The cardiac FGF23/FGF receptor (FGFR) system and its role in the development of LVH in humans have not been addressed previously. Methods: We conducted a retrospective case-control study in 24 deceased patients with childhood-onset end-stage renal disease (dialysis: n = 17; transplanted: n = 7), and 24 age- and sexmatched control subjects. Myocardial autopsy samples of the left ventricle were evaluated for expression of endogenous FGF23, FGFR isoforms, Klotho, calcineurin and nuclear factor of activated T-cells (NFAT) by immunohistochemistry, immunofluorescencemicroscopy, qRT-PCR and western blotting. Results: The majority of patients presented with LVH (67%). Human cardiomyocytes express full-length FGF23, and cardiac FGF23 is excessively high in patients with CKD. Enhanced myocardial expression of FGF23 in concert with Klotho deficiency strongly correlates with the presence of LVH. Cardiac FGF23 levels associate with time-averaged serum phosphate levels, up-regulation of FGFR4 and activation of the calcineurin-NFAT signaling pathway, an established mediator of cardiac remodelling and LVH. These changes are detected in patients on dialysis but not in those with a functioning kidney transplant. Conclusions: Our results indicate a strong association between LVH and enhanced expression levels of FGF23, FGFR4 and calcineurin, activation of NFAT and reduced levels of soluble Klotho in the myocardium of patients with CKD. These alterations are not observed in kidney transplant patients.
KW - Chronic kidney disease
KW - Fibroblast growth factor 23
KW - Fibroblast growth factor receptor 4
KW - Klotho
KW - Left ventricular hypertrophy
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U2 - 10.1093/ndt/gfv421
DO - 10.1093/ndt/gfv421
M3 - Article
C2 - 26681731
AN - SCOPUS:84983740565
VL - 31
SP - 1088
EP - 1099
JO - Nephrology Dialysis Transplantation
JF - Nephrology Dialysis Transplantation
SN - 0931-0509
IS - 7
ER -