Klotho: a link between cardiovascular and non-cardiovascular mortality

Abstract

Klotho is a membrane-bound protein acting as an obligatory coreceptor for fibroblast growth factor 23 (FGF23) in the kidney and parathyroid glands. The extracellular portion of its molecule may be cleaved and released into the blood and produces multiple endocrine effects. Klotho exerts anti-inflammatory and antioxidative activities that may explain its ageing suppression effects evidenced in mice; it also modulates mineral metabolism and FGF23 activities and limits their negative impact on cardiovascular system. Clinical studies have found that circulating Klotho is associated with myocardial hypertrophy, coronary artery disease and stroke and may also be involved in the pathogenesis of salt-sensitive hypertension with a mechanism sustained by inflammatory cytokines. As a consequence, patients maintaining high serum levels of Klotho not only show decreased cardiovascular mortality but also non-cardiovascular mortality. Klotho genetic polymorphisms may influence these clinical relationships and predict cardiovascular risk; rs9536314 was the polymorphism most frequently involved in these associations. These findings suggest that Klotho and its genetic polymorphisms may represent a bridge between inflammation, salt sensitivity, hypertension and mortality. This may be particularly relevant in patients with chronic kidney disease who have decreased Klotho levels in tissues and blood.

Keywords: FGF23; Klotho; ageing; all-cause mortality; cardiovascular mortality.

FIGURE 1

Effects of soluble Klotho and transmembrane Klotho in proximal and distal tubular cells. In proximal cells, transmembrane Klotho, included in a complex with FGF23 and FGFR, inhibits phosphate reabsorption and 1α-hydroxylation of 25-hydroxyvitamin D [25(OH)D]. In distal convoluted tubular cells, Klotho stimulates the phosphorylation of WNK4 and SGK1 and the expression of the sodium channel ENaC, potassium channel ROMK, NCC and calcium channel TRPV5. As a result, Klotho activates sodium and calcium reabsorption and potassium excretion through these carriers. Klotho sialidase activity was hypothesized to increase membrane expression of TRPV5 and ROMK in distal tubular cells. In addition, soluble Klotho increases FGF23 production in osteocytes. Arrows indicate activation and lines with a flat end indicate inhibition of the considered activity.

FIGURE 2

Klotho may suppress inflammation and oxidative stress in VSMCs and endothelial cells. Phosphate entry in VSMCs through PiT1 carrier stimulates the production of reactive oxygen species such as superoxide (${\mathrm{O}}_2^{-}$) and hydrogen peroxide (H₂O₂). These compounds activate nuclear factor-κB signalling pathways and increase the expression of osteogenic factors in VSMCs that are stimulated to develop an osteoblast-like phenotype. Thus these cells can release membrane vesicles containing hydroxyapatite crystals and cause artery wall calcification. In addition to these mechanisms, sodium overload increases sodium content in the artery wall. This causes local inflammation and production of ROS and O₂ in endothelial cells, impairing nitric oxide synthesis and its vasodilating activity.