Klotho and Phosphate Are Modulators of Pathologic Uremic Cardiac Remodeling

Abstract

Cardiac dysfunction in CKD is characterized by aberrant cardiac remodeling with hypertrophy and fibrosis. CKD is a state of severe systemic Klotho deficiency, and restoration of Klotho attenuates vascular calcification associated with CKD. We examined the role of Klotho in cardiac remodeling in models of Klotho deficiencygenetic Klotho hypomorphism, high dietary phosphate intake, aging, and CKD. Klotho-deficient mice exhibited cardiac dysfunction and hypertrophy before 12 weeks of age followed by fibrosis. In wild-type mice, the induction of CKD led to severe cardiovascular changes not observed in control mice. Notably, non-CKD mice fed a high-phosphate diet had lower Klotho levels and greatly accelerated cardiac remodeling associated with normal aging compared with those on a normal diet. Chronic elevation of circulating Klotho because of global overexpression alleviated the cardiac remodeling induced by either high-phosphate diet or CKD. Regardless of the cause of Klotho deficiency, the extent of cardiac hypertrophy and fibrosis correlated tightly with plasma phosphate concentration and inversely with plasma Klotho concentration, even when adjusted for all other covariables. High-fibroblast growth factor-23 concentration positively correlated with cardiac remodeling in a Klotho-deficient state but not a Klotho-replete state. In vitro, Klotho inhibited TGF-b1-, angiotensin II-, or high phosphate-induced fibrosis and abolished TGF-b1-or angiotensin II-induced hypertrophy of cardiomyocytes. In conclusion, Klotho deficiency is a novel intermediate mediator of pathologic cardiac remodeling, and fibroblast growth factor-23 may contribute to cardiac remodeling in concert with Klotho deficiency in CKD, phosphotoxicity, and aging.

Renal Production, Uptake, and Handling of Circulating αKlotho

“…aKlotho is found in urine and serum of rodents and humans 2,20,42,56 ; and the kidney has the highest abundance of aKlotho compared with other organs. Clinical and experimental animal studies showed low renal tubular aKlotho expression in both acute kidney injury and CKD 10,40,42,43,[56][57][58][59][60][61][62] and low circulating aKlotho levels in kidney diseases of a variety of etiologies in animals 42,43,56,62 and humans. 32,44,61,63 These data suggest that the kidney contributes to circulating aKlotho.…”

Fibroblast Growth Factor‐23 and Heart Failure With Reduced Versus Preserved Ejection Fraction: MESA

“…Other mechanisms by which FGF‐23 could lead to adverse cardiovascular consequences include calcitriol deficiency, altered phosphorus homeostasis, systemic inflammation and oxidative stress, and sodium retention 31, 32, 33. Additionally, FGF‐23 may downregulate soluble α‐klotho,34 an enzyme with anti‐aging effects that was shown to protect the heart against cardiac hypertrophy and cardiac remodeling 35, 36. In a study by Reindl et al, FGF‐23 was significantly higher in patients who developed LV remodeling post ST‐segment–elevation myocardial infarction even after adjustment for biomarkers of myocardial necrosis, myocardial stress, and inflammation 37.…”

Mineral (Mal)Adaptation to Kidney Disease—Young Investigator Award Address

“…Rather than embracing approaches that target reduction of FGF-23 or phosphate at the expense of elevated levels of the other, we need to develop therapeutic strategies that address both phosphate and FGF-23 excess simultaneously (76). Ideally, optimal interventions will also increase renal expression of a-klotho, deficiency of which is also implicated in the pathogenesis of both arterial calcification and LVH (77,78).…”