Enhanced Klotho availability protects against cardiac dysfunction induced by uraemic cardiomyopathy by regulating Ca²⁺ handling

Abstract

Background and Purpose Klotho is a membrane‐bound or soluble protein, originally identified as an age‐suppressing factor and regulator of mineral metabolism. Klotho deficiency is associated with the development of renal disease, but its role in cardiac function in the context of uraemic cardiomyopathy is unknown. Experimental Approach We explored the effects of Klotho on cardiac Ca2+ cycling. We analysed Ca2+ handling in adult cardiomyocytes from Klotho‐deficient (kl/kl) mice and from a murine model of 5/6 nephrectomy (Nfx). We also studied the effect of exogenous Klotho supplementation, by chronic recombinant Klotho treatment, or endogenous Klotho overexpression, using transgenic mice overexpressing Klotho (Tg‐Kl), on uraemic cardiomyopathy. Hearts from Nfx mice were used to study Ca2+ sensitivity of ryanodine receptors and their phosphorylation state. Key Results Cardiomyocytes from kl/kl mice showed decreased amplitude of intracellular Ca2+ transients and cellular shortening together with an increase in pro‐arrhythmic Ca2+ events compared with cells from wild‐type mice. Cardiomyocytes from Nfx mice exhibited the same impairment in Ca2+ cycling as kl/kl mice. Changes in Nfx cardiomyocytes were explained by higher sensitivity of ryanodine receptors to Ca2+ and their increased phosphorylation at the calmodulin kinase type II and protein kinase A sites. Ca2+ mishandling in Nfx‐treated mice was fully prevented by chronic recombinant Klotho administration or transgenic Klotho overexpression. Conclusions and Implications Klotho emerges as an attractive therapeutic tool to improve cardiac Ca2+ mishandling observed in uraemic cardiomyopathy. Strategies that improve Klotho availability are good candidates to protect the heart from functional cardiac alterations in renal disease.

Genetic Deletion of NOD1 Prevents Cardiac Ca2+ Mishandling Induced by Experimental Chronic Kidney Disease

“…In this regard, Wt -Nx cardiomyocytes showed an increase in diastolic Ca 2+ leak represented by a higher frequency of Ca 2+ sparks, Ca 2+ waves and spontaneous Ca 2+ transients, as compared with Wt -sham cells. Supporting these results, we previously showed that RyR 2 channel activity is increased in hearts from Wt -Nx mice [ 48 ]. The increased diastolic Ca 2+ leak observed in Wt -Nx mice is potentially a good substrate for the induction of cardiac arrhythmias since the released Ca 2+ diffuses to neighboring RyR 2 clusters inducing SCR and triggering cardiac arrhythmias.…”

“…We show that deficiency of NOD1 prevents cardiac Ca 2+ mishandling in a mouse model of CKD induced by 5/6 nephrectomy, suggesting a specific protective cardiac role of this receptor independent of renal damage. The classical 5/6 nephrectomy model of CKD reproduces many of the main features found in human CKD [ 46 , 47 ] and we recently showed that this model presents with elevated cardiac Ca 2+ mishandling, which can explain the cardiac dysfunction that accompanies CKD [ 48 ]. Interestingly, the altered pattern of Ca 2+ cycling in cardiomyocytes in nephrectomised Wt mice has important similarities to that found in HF [ 11 , 49 ], where cardiomyocyte contraction is also strongly compromised.…”

“…Six-week-old male were randomly assigned to either five-sixth nephrectomy (Nx) or sham surgery under isoflurane (1.5% v/v , isoflurane/oxygen) anesthesia and preoperative analgesia (Metacam, 0.05 mg/kg intramuscular) in a two-stage approach, as described [ 48 ]. Briefly, in the first stage an abdominal midline incision was made and the left kidney was exposed.…”

An Overview of FGF-23 as a Novel Candidate Biomarker of Cardiovascular Risk

“…Similar results related to cardiac dysfunction and predisposition to ventricular arrhythmia were found in nephrectomised mice and homozygous Klotho-hypomorphic (kl/kl) mice, both of which are experimental animal models that have middle (∼300 pg/mL) or very high (∼400.000 pg/mL) circulating FGF-23 levels (Navarro-García et al, 2020). Interestingly, when these mice are treated with recombinant Klotho, cardiac dysfunction and pro-arrhythmogenic Ca 2+ release events are prevented (Navarro-García et al, 2020). This highlights the possible protection of Klotho against the deleterious effects of FGF-23.…”

“…It is also important to mention that soluble Klotho could act as a circulating lure for FGF-23, impeding its binding to cardiac FGFRs; act as a coreceptor in cardiomyocytes, causing a switch in or even the blockade of the FGF-23 signalling pathway; or interact with an unknown receptor activating the cardiac protective signalling pathway. Thus, Klotho could block or reduce the hypertrophic effect of FGF-23 on the heart, as it does with the deleterious effect of FGF-23 on cardiac function ( Navarro-García et al, 2019 , 2020 ). Indeed, several authors have shown the cardioprotective action of recombinant supplementation with Klotho in several experimental models of direct or indirect cardiac damage ( Xie et al, 2012 ; Hu et al, 2017 ; Liu et al, 2019 ; Navarro-García et al, 2019 , 2020 ; Wright et al, 2019 ; Han et al, 2020 ).…”