The anti-aging factor Klotho protects against acquired long QT syndrome induced by uremia and promoted by fibroblast growth factor 23

• Published in: BMC medicine 2022-01, Vol.20 (1), p.14-14, Article 14
• Main Authors: Navarro-García, José Alberto, Salguero-Bodes, Rafael, González-Lafuente, Laura, Martín-Nunes, Laura, Rodríguez-Sánchez, Elena, Bada-Bosch, Teresa, Hernández, Eduardo, Mérida-Herrero, Evangelina, Praga, Manuel, Solís, Jorge, Arribas, Fernando, Bueno, Héctor, Kuro-O, Makoto, Fernández-Velasco, María, Ruilope, Luis Miguel, Delgado, Carmen, Ruiz-Hurtado, Gema
• Format: Article
• Language: English
• Subjects: Aging; Analysis; Animal models; Animals; Biochemistry; Cardiac arrhythmia; Cardiomyocytes; Cardiovascular disease; Cardiovascular diseases; Care and treatment; Chronic kidney failure; CKD; Complications and side effects; Dialysis; Electrocardiography; FGF23; Fibroblast Growth Factor-23; Fibroblast growth factors; Fibroblast Growth Factors - genetics; Fibroblasts; Glucuronidase - genetics; Growth factors; Heart; Hemodialysis; Hemodialysis patients; Humans; Hypertension; Kidney diseases; Klotho; Klotho protein; Klotho Proteins; Laboratories; Long QT; Long QT Syndrome; Metabolism; Mice; Mortality; Nephrectomy; Patients; Potassium; Potassium channels; Potassium channels (voltage-gated); Prevention; Prolongation; Renal Insufficiency, Chronic - complications; Risk factors; Surgery; Therapeutic targets; Uremia; Uremia - complications; Ventricle
• ISSN: 1741-7015; 1741-7015
• DOI: 10.1186/s12916-021-02209-9

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. 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. 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 (I ), 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 I current. Likewise, administration of recombinant Klotho blocked the downregulation of Kv4.2 expression in Nfx mice and in FGF23-exposed cardiomyocytes. 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.