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Loss of Klotho in CKD Breaks One’s Heart

Haiyan Fu and Youhua Liu
JASN October 2015, 26 (10) 2305-2307; DOI: https://doi.org/10.1681/ASN.2015020200
Haiyan Fu
*State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China; and
†Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Youhua Liu
†Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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  • CKD
  • cardiovascular disease
  • left ventricular hypertrophy

CKD is increasingly recognized as a public health challenge worldwide, and it is associated with high rates of morbidity, mortality, and health care expenditure. A growing body of evidence indicates that decline in renal function, per se, is also a strong and independent risk factor for developing cardiovascular disease (CVD). Patients with CKD display increased rates of left ventricular hypertrophy (LVH), atherosclerotic coronary artery disease, myocardial infarction, cardiac fibrosis, and sudden death.1 Notably, patients with CKD on dialysis often die of cardiovascular complications. Although there is clear appreciation of the close relationship between renal insufficiency and increased cardiovascular events in the medical community, the mechanisms underlying such an alarming prevalence of CVD in patients with CKD remain poorly understood.

Both CKD and CVD share numerous common risk factors, such as hypertension, age, diabetes mellitus, obesity, and dyslipidemia. However, these factors cannot fully explain the startling prevalence of CVD in CKD. Clinical studies have shown that even modest reductions in renal function could lead to an increased incidence of CVD,2 suggesting that loss of functional nephron might directly contribute to the development of cardiovascular morbidity. There are a variety of uremia–specific nontraditional risk factors in CKD that may be implicated in the pathogenesis of cardiovascular complications, including the presence of protein–bound uremic toxins, such as indoxyl sulfate (IS), low serum level of Klotho, albuminuria, hyperactive renin-angiotensin-aldosterone system (RAAS), and abnormal bone and mineral metabolism.3–5 Systematic delineation of the relative importance and complex interaction of these risk factors for CVD in patients with CKD is a daunting task, but such knowledge is necessary and paramount in developing effective strategies for alleviating CKD–associated cardiovascular complications in the clinical setting.

In this issue of JASN, Yang et al.6 investigated the potential role and mechanisms of antiaging protein Klotho in ameliorating IS–induced myocardial hypertrophy. By analyzing clinical data, Yang et al.6 showed that, in a cohort of 86 patients with CKD, there was an inverse correlation between serum levels of IS and Klotho. Yang et al.6 further showed that chronic IS infusion repressed Klotho expression and caused LVH in otherwise healthy mice. Klotho haploinsufficiency in heterozygous Klotho–deficient mice further aggravated IS-induced LVH, whereas administration of exogenous Klotho alleviated LVH. In vitro studies showed that Klotho prevented cardiomyocyte hypertrophy by blocking IS–induced reactive oxygen species (ROS)–mediated p38 mitogen–activated protein kinase (MAPK) and extracellular signal–regulated kinase 1/2 signaling.6 These studies establish that an imbalance between circulating Klotho and IS contributes to the development of LVH in patients with CKD. Although both an increased IS level in serum and Klotho deficiency have been individually linked to myocardial hypertrophy in CKD,7,8 this study by Yang et al.6 provides comprehensive analyses of the intrinsic interplay between these two factors in mediating cardiovascular complications. In this context, the study is interesting, timely, and of clinical relevance, and Yang et al.6 are to be congratulated for their valuable contribution to the field.

Klotho is a single–pass transmembrane protein that is highly expressed in renal tubular epithelium of normal adult kidneys.3,9,10 Klotho is best known for its antiaging effect and its function as the coreceptor for fibroblast growth factor 23 (FGF-23), a bone-derived hormone that plays a critical role in phosphate homeostasis. There are two forms of Klotho in the body: the full-length membranous form and the truncated, secreted form. The latter is generated from alternative splicing and/or proteolytic shedding of the extracellular domains of membranous Klotho. Notably, secreted Klotho is soluble and present in the circulation, and therefore, it can exert its biologic actions in remote organs. Secreted Klotho may, thus, be viewed as a hormone.

The heart is known to express little, if any, Klotho protein. Recent studies using a genetic approach have unambiguously confirmed that kidney is the principal contributor of circulating Klotho.11 In harmony with this notion, mice with kidney-specific ablation of Klotho exhibit severe growth retardation, kyphosis, and premature death, closely resembling the phenotype of global Klotho knockout mice.11 It is conceivable that, in the uremic conditions of CKD, the kidney loses its ability to produce and secrete Klotho protein,3,10 and therefore, the circulating level of Klotho protein is progressively reduced. Such a state of Klotho deficiency in CKD would diminish the cardioprotection by Klotho and thereby, render the heart susceptible to developing CKD-associated CVD and cardiovascular complications.5 Along this line, it is plausible that the loss of Klotho could be a logical explanation for the missing link between CKD and its high incidence of cardiovascular complications.

The study by Yang et al.6 has illustrated a complex, reciprocal interplay between Klotho and IS, a common uremic toxin found in the circulation of patients with CKD. IS in serum is typically protein bound, making it difficult to be eliminated by dialysis, and thus, the serum level of IS in patients with CKD is progressively increased as disease deteriorates. Such a high circulating level of IS seems to be detrimental to both the kidneys and the heart by numerous mechanisms. For the kidneys, elevated serum level of IS alone after repeated injections is sufficient to suppress Klotho expression and induces kidney injury and fibrosis. Although exactly how IS represses Klotho expression in vivo remains to be investigated, a decreased production of Klotho in the kidneys is almost certain to result in its deficiency in the circulation. Therefore, the heart in patients with advanced CKD will endure double hits. On one hand, elevated IS directly induces cardiomyocyte hypertrophy, leading to an increased left ventricular mass and impaired cardiac function, a condition that occurs in up to 95% of patients with CKD.1,2 On the other hand, Klotho deficiency in CKD will remove an endogenous cardioprotective mechanism and render the heart vulnerable to additional IS injury, thereby creating a vicious cycle.6

It should be pointed out that Klotho is a well characterized coreceptor for FGF-23 and participates in regulating phosphate metabolism. In this regard, the decreased level of Klotho in CKD may also cause cardiomyopathy through increases in serum FGF-23 and/or phosphate levels.12 However, recent studies show that normalization of serum phosphate and FGF-23 levels fails to abrogate cardiac hypertrophy in Klotho–deficient CKD mice, suggesting that Klotho prevents uremic cardiomyopathy by a mechanism independent of FGF-23 and phosphate.4 These observations together with the study by Yang et al.6 underscore that the cardioprotection of Klotho is most likely mediated by its direct action on cardiomyocytes. Indeed, although the molecular details remain to be delineated, Klotho was shown to prevent IS–induced, ROS–mediated MAPK activation and cell hypertrophy in cultured cardiac myocytes.6 Therefore, targeting the IS–triggered ROS/MAPK signaling pathway may represent a major mechanism by which Klotho prevents cardiac hypertrophy and cardiovascular complications.

Mounting evidence indicates that Klotho is a multifunctional protein that regulates several pivotal signaling pathways, and therefore, its cardioprotective actions in CKD in vivo might be much more complex than targeting ROS/MAPK alone. In addition to interacting with FGF-23, recent studies show that secreted Klotho is able to bind to Wnt ligands, TGF-β type II receptor and FGF receptor-1, respectively, thereby modulating these pathogenic signaling.3,13,14 Because Wnt/β-catenin is a master regulator that controls the expression of multiple RAAS components,15 loss of Klotho in CKD would lead to hyperactivation of RAAS through derepressing Wnt/β-catenin. This will lead to salt and water retention, thereby promoting pressure and volume overload and hypertension, all of which could contribute to LVH. Consistently, chronic infusion of angiotensin II alone, the active component of RAAS, is sufficient to induce LVH. Therefore, apart from blocking ROS/MAPK signaling, the possibility also exists that Klotho may protect the heart against developing LVH by a multitude of other mechanisms, such as inhibiting Wnt/β-catenin, TGF-β, and FGF-2 signaling. These issues deserve to be investigated in the future.

Although distant from each other, the kidney and the heart constantly engage in cross-talk through circulating factors. This study by Yang et al.6 shows that Klotho deficiency in the uremic state is a key factor mediating aberrant kidney and heart interactions. Such insights, as provided by this interesting study by Yang et al.,6 may lead to translational studies aimed at lowering CVD events and mortality in patients with CKD.

Disclosures

None.

Acknowledgments

Work was supported by National Science Foundation of China Grant 81130011 and National Institutes of Health Grants DK064005 and DK091239.

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

  • See related article, “Klotho Protects Against Indoxyl Sulphate-Induced Myocardial Hypertrophy,” on pages 2434–2446.

  • Copyright © 2015 by the American Society of Nephrology

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Journal of the American Society of Nephrology
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Loss of Klotho in CKD Breaks One’s Heart
Haiyan Fu, Youhua Liu
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Haiyan Fu, Youhua Liu
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