Kidney Week

Abstract: TH-OR041

High Fibroblast Growth Factor 23 Levels Induce Ventricular Arrhythmogenesis via Intracellular Ca²⁺ Mishandling

Session Information

• Bone and Mineral Metabolism: Basic Research
  November 07, 2019 | Location: 145, Walter E. Washington Convention Center
  Abstract Time: 04:30 PM - 04:42 PM

Category: Bone and Mineral Metabolism

• 401 Bone and Mineral Metabolism: Basic

Authors

• Navarro-Garcia, Jose Alberto, Research Institute 1+12, Hospital Universitario 12 de Octubre, Madrid, Madrid, Spain

Jose Alberto Navarro-Garcia, MS



Experimental researcher of Cardiorenal Translational Laboratory. Cardiovascular Area. Translational Research in Hypertension and Cardiorenal Disease Group. Institute of Research i+12. Hospital Universitario 12 de Octubre , Madrid, Spain. Graduated in Biology in 2012 from the Biological Sciences Faculty of Universidad Complutense de Madrid (UCM) and obtained the Master's degree of Research in Inmunology in 2014 at the Medicine Faculty of Universidad Complutense de Madrid (UCM). I started PhD studies in 2016. My research activities focus on the study of new molecular targets and biomarkers involved in hypertension, cardiovascular and renal disease. I am member of Spanish Society of Nephrology (SEN).

• Delgado, Carmen, Research Institute Alberto Sols, CSIC, Madrid, Spain

Carmen Delgado,

• Fernandez velasco, Maria, Research Institute Idipaz, Hospital Universitario La Paz, Madrid, Madrid, Spain

Maria Fernandez velasco,

• Rodríguez-Sánchez, Elena, Research Institute 1+12, Hospital Universitario 12 de Octubre, Madrid, Madrid, Spain

Elena Rodríguez-Sánchez,

• Aceves-Ripoll, Jennifer, Research Institute 1+12, Hospital Universitario 12 de Octubre, Madrid, Madrid, Spain

Jennifer Aceves-Ripoll,

• González, Laura, Research Institute 1+12, Hospital Universitario 12 de Octubre, Madrid, Madrid, Spain

Laura González,

• Kuro-o, Makoto, Jichi Medical University, Shimotsuke, Japan

Makoto Kuro-o,

• Ruilope, Luis M., Research Institute 1+12, Hospital Universitario 12 de Octubre, Madrid, Spain

Luis M. Ruilope,

• Ruiz-Hurtado, Gema, Research Institute 1+12, Hospital Universitario 12 de Octubre, Madrid, Madrid, Spain

Gema Ruiz-Hurtado,

Group or Team Name

• Cardiorenal Translational Laboratory

Background

Fibroblast growth factor (FGF)23 is a phosphaturic hormone synthesized as response to increased serum phosphate levels. FGF23 action requires the presence of its cofactor Klotho (KL). Chronic kidney disease patients show decreased soluble KL and high FGF23 levels. High FGF23 levels have been associated to renal dysfunction and recently considered as a non-conventional cardiovascular risk factor. However, it is unknown whether FGF23 might alter cardiac contractile function and rhythm.Our study analyze FGF23 effect on calcium (Ca²⁺) handling, key regulator of contractile function and ventricular rhythm, and the Ca²⁺ handling in an animal model with high circulating levels of FGF23 (KL hypomorphic mice, kl/kl).

Methods

Isolated adult rat ventricular myocytes (ARVM) were perfused with FGF23 (100 ng/mL). To determinate FGF23-dependent pathways, ARVM were pre-incubated with the FGF-receptor inhibitor PD173074 (10 mM) or recombinant KL (rKL; 100 ng/mL). Adult mouse ventricular myocytes (AMVM) were isolated from Wildtype (WT, +/+) and kl/kl littermates mice. L-type Ca²⁺ current (I_CaL) was recorded by the whole-cell patch-clamp technique. Ca²⁺ handling and contractile function were analyzed using confocal microscopy.

Results

FGF23 reduced I_CaL (p<0.001), intracellular systolic Ca²⁺ transients amplitude (p<0.01) and sarcoplasmic reticulum (SR) Ca²⁺ load (p<0.01). These alterations were functionally translated to a deterioration of cellular contraction (p<0.01). FGF23 exposure increased diastolic Ca²⁺ leak (p<0.01) and ryanodine receptors activity. FGF23 perfusion induced a pro-arrhythmogenic phenotype in paced ARVM (p<0.05). FGF23 effects were blocked in PD173074- or rKL-pretreated ARVM. Moreover, kl/kl mice showed a significant increment of FGF23 serum levels versus WT (p<0.001). kl/kl AMVM presented a reduction of intracellular systolic Ca²⁺ transient amplitude (p<0.001), contraction (p<0.001) and SR-Ca²⁺ load (p<0.05). Diastolic Ca²⁺ release was increased in kl/k (p<0.01) which lead finally to a pro-arrhythmogenic phenotype in kl/kl AMVM (p<0.001).

Conclusion

Our study uncovers FGF23 as new target in the intracellular Ca²⁺ handling, able to induce contractile dysfunction and pro-arrhythmogenic phenotype in adult cardiomyocytes.

Funding

• Private Foundation Support