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

Abstract

Background 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. Graphical abstract

Soluble α-klotho and heparin modulate the pathologic cardiac actions of fibroblast growth factor 23 in chronic kidney disease

“…69 Furthermore, we found that administration of sKL protects a mouse model of CKD from developing ventricular arrhythmias. 79 Combined, these studies indicate that sKL can directly inhibit the pathologic actions of FGF23 on cardiac myocytes, suggesting the potential for sKL administration as a novel cardioprotective therapy that might be effective in scenarios of systemic FGF23 elevations, such as CKD. However, attempts from various groups to purify sKL protein in larger amounts have failed, and sKL protein appears to be highly unstable.…”

“…Several studies have shown that elevated sKL levels in animal models of CKD have cardioprotective effects. 54,56,58,78,79 A recent study suggests that these effects are independent of sKL's antihypertensive effects and are rather based on the direct actions of sKL on the heart. 80 To determine whether sKL interferes with the direct effects of FGF23 on cardiac myocytes, we treated isolated NRVMs with FGF23 for 48 hours, which induced hypertrophic growth as determined by an increase in the area of immunolabeled cells (Figure 2a), as shown before.…”

Partial Genetic Deletion of Klotho Aggravates Cardiac Calcium Mishandling in Acute Kidney Injury

“…These opposite results could be explained by the fact that the relation between kidney function and soluble klotho is not closely linear, depending on the time in which klotho is measured after AKI. At the cardiac level, there is evidence that klotho exerts a cardioprotective role, since its deficit is linked to uremic cardiac remodelling [ 40 ] and its exogenous supplementation protects the cardiac function [ 18 , 24 ]. Here, we demonstrated that a partial klotho deficiency that occurs with any evidence of renal disease, could have an added deleterious impact in the setting of AKI.…”

“…Recently, it has been demonstrated that several uremic experimental models develop a cardiac failure phenotype with relevant cardiomyocyte alterations including contractile dysfunction and intracellular calcium (Ca 2+ ) mishandling [ 18 , 19 , 20 , 21 ]. In this uremic cardiomyopathy setting, klotho has emerged as a new therapeutic target to protect cardiac function by normalising intracellular Ca 2+ handling in ventricular cardiomyocytes, where endogenous klotho overexpression or increasing its bioavailability exogenously through recombinant murine klotho administration improves cardiomyocyte function and impedes deleterious cardiac remodelling associated with renal damage [ 20 , 22 , 23 , 24 ]. On the other hand, a severe klotho deficiency, as happens in hypomorphic kl/kl mice, significantly worsens cardiomyocyte function, inducing a deleterious ionic remodelling that predisposes them to suffer heart failure and fatal ventricular arrhythmias even in the absence of any additional renal insult [ 18 , 24 ].…”

“…In this uremic cardiomyopathy setting, klotho has emerged as a new therapeutic target to protect cardiac function by normalising intracellular Ca 2+ handling in ventricular cardiomyocytes, where endogenous klotho overexpression or increasing its bioavailability exogenously through recombinant murine klotho administration improves cardiomyocyte function and impedes deleterious cardiac remodelling associated with renal damage [ 20 , 22 , 23 , 24 ]. On the other hand, a severe klotho deficiency, as happens in hypomorphic kl/kl mice, significantly worsens cardiomyocyte function, inducing a deleterious ionic remodelling that predisposes them to suffer heart failure and fatal ventricular arrhythmias even in the absence of any additional renal insult [ 18 , 24 ]. However, it remains unclear whether a moderate decrease in klotho expression could predispose a cardiac outcome after renal damage.…”