RT Journal Article
T1 The anti-aging factor Klotho protects against acquired long QT syndrome induced by uremia and promoted by fibroblast growth factor 23
A1 Navarro García, José Alberto
A1 Salguero Bodes, Rafael
A1 Praga Terente, Manuel
A1 Arribas Ynsaurriaga, Fernando
A1 Bueno Zamora, Héctor José
A1 Ruilope Urioste, Luis Miguel
A1 Ruiz Hurtado, Gema
AB AbstractBackground: Chronic kidney disease (CKD) is associated with increased propensity for arrhythmias. In this context, ventricular repolarization alterations have been shown to predispose to fatal arrhythmias and sudden cardiac death. Between mineral bone disturbances in CKD patients, increased fibroblast growth factor (FGF) 23 and decreased Klotho are emerging as important effectors of cardiovascular disease. However, the relationship between imbalanced FGF23-Klotho axis and the development of cardiac arrhythmias in CKD remains unknown.Methods: We carried out a translational approach to study the relationship between the FGF23-Klotho signaling axis and acquired long QT syndrome in CKD-associated uremia. FGF23 levels and cardiac repolarization dynamics were analyzed in patients with dialysis-dependent CKD and in uremic mouse models of 5/6 nephrectomy (Nfx) and Klotho deficiency (hypomorphism), which show very high systemic FGF23 levels.Results: Patients in the top quartile of FGF23 levels had a higher occurrence of very long QT intervals (> 490 ms) than peers in the lowest quartile. Experimentally, FGF23 induced QT prolongation in healthy mice. Similarly, alterations in cardiac repolarization and QT prolongation were observed in Nfx mice and in Klotho hypomorphic mice. QT prolongation in Nfx mice was explained by a significant decrease in the fast transient outward potassium (K+) current (Itof), caused by the downregulation of K+ channel 4.2 subunit (Kv4.2) expression. Kv4.2 expression was also significantly reduced in ventricular cardiomyocytes exposed to FGF23. Enhancing Klotho availability prevented both long QT prolongation and reduced Itof current. Likewise, administration of recombinant Klotho blocked the downregulation of Kv4.2 expression in Nfx mice and in FGF23-exposed cardiomyocytes.Conclusion: The FGF23-Klotho axis emerges as a new therapeutic target to prevent acquired long QT syndrome in uremia by minimizing the predisposition to potentially fatal ventricular arrhythmias and sudden cardiac death in patients with CKD.
PB BioMed Central
YR 2022
FD 2022
LK https://hdl.handle.net/20.500.14352/130497
UL https://hdl.handle.net/20.500.14352/130497
LA eng
NO Navarro-García JA, Salguero-Bodes R, González-Lafuente L, Martín-Nunes L, Rodríguez-Sánchez E, Bada-Bosch T, Hernández E, Mérida-Herrero E, Praga M, Solís J, Arribas F, Bueno H, Kuro-O M, Fernández-Velasco M, Ruilope LM, Delgado C, Ruiz-Hurtado G. The anti-aging factor Klotho protects against acquired long QT syndrome induced by uremia and promoted by fibroblast growth factor 23. BMC Med. 2022 Jan 19;20(1):14. doi: 10.1186/s12916-021-02209-9. PMID: 35042527; PMCID: PMC8767669.
NO Cofinanciado con Fondos FEDER
NO European Commission
NO Ministerio de Economía y Competitividad (España)
NO Instituto de Salud Carlos III (España)
NO Sociedad Española de Cardiología
NO Fundación Renal Íñigo Alvarez de Toledo
DS Docta Complutense
RD 18 abr 2026