ESPN 50th Annual Meeting

ESPN 2017


 
CARDIAC FGF23 IS STIMULATED BY RAAS ACTIVATION AND INDUCES A PRO-FIBROTIC CROSSTALK BETWEEN CARDIAC MYOCYTES AND FIBROBLASTS
MAREN LEIFHEIT-NESTLER 1 FELIX KIRCHHOFF 1 JULIA NESPOR 1 BEATRICE RICHTER 3 Joerg Heineke 2 Dieter Haffner 1

1- DEPARTMENT OF PEDIATRIC KIDNEY, LIVER AND METABOLIC DISEASES, HANNOVER MEDICAL SCHOOL, HANNOVER, GERMANY
2- Department of Cardiology and Angiology, Rebirth-Cluster of Excellence, Hannover Medical School, Hannover, Germany
3- Department of Medicine and Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL, USA
 
Introduction:

FGF23 is discussed as a new biomarker associated with cardiac hypertrophy and mortality in patients with CKD, heart failure, and cardiogenic shock that promotes diastolic dysfunction, congestive heart failure, arrhythmia, and sudden death. Since we previously demonstrated that FGF23 is expressed by cardiac myocytes, enhanced in CKD, and causes cardiac hypertrophy via activation of FGFR4/calcineurin/NFAT signaling, we aimed to investigate whether induction of cardiac FGF23 associates with myocardial fibrosis in uremia and directly promotes pro-fibrotic crosstalk of cardiac myocytes and fibroblasts in vitro.

Material and methods:

We conducted a retrospective case-control study including 24 myocardial autopsy samples from CKD patients and investigated cardiac fibrosis by histological quantification of fibrillar collagens and fibrosis RT2 profiler PCR array analyzes. Data were correlated with clinical parameters, cardiac FGF23, and klotho levels. The specific impact of FGF23-mediated induction of cardiac fibrosis was further evaluated in isolated cardiac fibroblasts and myocytes.

Results:

Accumulation of fibrillar collagens was increased in myocardial tissue of CKD patients and correlated with duration of dialysis, klotho deficiency, and enhanced angiotensinogen expression. TGF-β and its related TGF-β receptor/Smad complexes, extracellular matric remodeling enzymes, as well as pro-fibrotic growth factors were significantly upregulated in myocardial tissue of dialysis patients. In cultured cardiac fibroblasts, FGF23 stimulated pro-fibrotic TGF-β receptor/Smad complexes and collagen synthesis, whereas treatment of isolated cardiac myocytes with FGF23 resulted in enhanced collagen remodeling, induction of pro-survival pathways, pro-inflammatory and pro-hypertrophic genes. Angiotensin II and aldosterone, as components of the renin-angiotensin-aldosterone system (RAAS), strongly induced FGF23 in cardiac myocytes and FGF23 further stimulated angiotensinogen expression in both cardiac cell types.

Conclusions:

Cardiac FGF23 is stimulated by RAAS components in cardiac myocytes to directly promote fibrotic and hypertrophic response. Secreted by cardiac myocytes, FGF23 induces pro-fibrotic pathways and collagen synthesis in cardiac fibroblasts in a paracrine fashion, suggesting that FGF23 impact on both pathological cardiac remodeling processes.