Enhanced Klotho Availability Protects Against Cardiac Dysfunction Induced by Uraemic Cardiomyopathy by Regulating Ca Handling

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 Ca cycling. We analysed Ca 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 Ca sensitivity of ryanodine receptors and their phosphorylation state.

Key Results: Cardiomyocytes from kl/kl mice showed decreased amplitude of intracellular Ca transients and cellular shortening together with an increase in pro-arrhythmic Ca events compared with cells from wild-type mice. Cardiomyocytes from Nfx mice exhibited the same impairment in Ca cycling as kl/kl mice. Changes in Nfx cardiomyocytes were explained by higher sensitivity of ryanodine receptors to Ca and their increased phosphorylation at the calmodulin kinase type II and protein kinase A sites. Ca 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 Ca mishandling observed in uraemic cardiomyopathy. Strategies that improve Klotho availability are good candidates to protect the heart from functional cardiac alterations in renal disease.