ESPN 50th Annual Meeting

ESPN 2017


 
Impact of FGF23 excess and klotho deficiency on cardiac remodeling: lessons from two mouse models
MAREN LEIFHEIT-NESTLER 1 BEATRICE RICHTER 2 MELIS BASARAN 1 Ioana Alesutan 3 Jakob Voelkl 3 Florian Lang 4 DIETER HAFFNER 1

1- DEPARTMENT OF PEDIATRIC KIDNEY, LIVER AND METABOLIC DISEASES, HANNOVER MEDICAL SCHOOL, HANNOVER, GERMANY
2- Department of Medicine and Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL, USA
3- Department of Internal Medicine and Cardiology, Center for Cardiovascular Research, Charité University Medicine, Berlin, Germany
4- Department of Internal Medicine III, University of Tübingen, Tübingen, Germany
 
Introduction:

Clinical and experimental studies associate FGF23 excess, high phosphate and PTH levels, and deficiency of active vitamin D (1,25D) and klotho with the development of cardiovascular events, e.g. endothelial dysfunction, left ventricular hypertrophy (LVH), and myocardial fibrosis. However, 1,25D and klotho ameliorate myocardial hypertrophy in vivo, and klotho suppresses cardiac fibroblast activation and collagen synthesis, and protects against FGF23-mediated oxidative stress in vitro.

Material and methods:

We investigated the cardiac phenotype in two mouse models of FGF23 excess and klotho deficiency, i) klotho hypomorphic (Kl-/-) mice presenting with high plasma levels of phosphate, 1,25D, and FGF23, as well as suppressed PTH, and ii) Hyp mice presenting with elevated FGF23 and PTH, but low phosphate and 1,25D levels in parallel with reduced renal klotho expression.

Results:

In both mouse models relative heart weight and cross-sectional area of individual cardiac myocytes were larger than in respective wild-type controls. In Kl-/- mice, cardiac Fgf23, Fgfr4 and calcineurin/NFAT signaling as well as pro-hypertrophic genes Rcan1, BNP, ANP, bMHC were clearly induced. Investigation of transcription factors and fibrosis-related molecules characteristic for pathological cardiac remodeling processes demonstrated enhanced expression of Cebpb and Gata4, as well as Tgfb1, collagen I, and Mmp2 in Kl-/- mice. In contrast, Hyp mice showed significantly enhanced cardiac Fgf23 mRNA levels and high intact cardiac Fgf23 protein, but the induction of Fgfr4/calcineurin/NFAT pathway, BNP, ANP and bMHC expression, and stimulation of pro-fibrotic factors was absent when compared to respective wild-type controls.

Conclusions:

Our data suggest that despite of high circulating and cardiac FGF23 levels and enhanced PTH, as well as reduced renal klotho and 1,25D synthesis, Hyp mice appear to be protected against the development of cardiac pathology possibly at least partly due to hypophosphatemia. In contrast, Kl-/- mice present with strong induction of cardiac hypertrophy and fibrosis despite high 1,25D plasma levels.