Klotho was originally identified as an anti-aging gene that accelerated aging when disrupted and extended life span when overexpressed in mice. The Klotho gene encodes a single-pass transmembrane protein and is expressed in the kidney and parathyroid gland. Klotho protein functions as an obligate subunit of the receptor for fibroblast growth factor 23 (FGF23). FGF23 is a hormone secreted from osteocytes and osteoblasts and acts on renal tubular cells to promote phosphate excretion into the urine and suppress synthesis of active form of vitamin D (1,25-dihydroxyvitamin D3;1,25(OH)(2)D(3)). Decreased Klotho expression due to the kidney damage including CKD might increase the circulating level of FGF23 and trigger disturbed mineral-bone metabolism, leading to CKD-MBD. Characteristic features of CKD-MBD including hyperphosphatemia, hypocalcemia, and decreased serum 1,25(OH)(2)D(3) can be explained by (mal) adaptation of the Klotho-FGF23 system, which also contributes to the pathophysiology of secondary hyperparathyroidism (SHPT). In addition to its function as a receptor for FGF23, the extracellular domain of Klotho is secreted by ectodomain shedding and functions as a humoral factor that regulates multiple ion channels and transporters. Thus, Klotho has emerged as a key regulator of mineral metabolism in health and disease.
The fibroblast growth factor (FGF) 19 subfamily of ligands, FGF19, FGF21, and FGF23, function as hormones that regulate bile acid, fatty acid, glucose, and phosphate metabolism in target organs through activating FGF receptors (FGFR1-4). We demonstrated that Klotho and betaKlotho, homologous single-pass transmembrane proteins that bind to FGFRs, are required for metabolic activity of FGF23 and FGF21, respectively. Here we show that, like FGF21, FGF19 also requires betaKlotho. Both FGF19 and FGF21 can signal through FGFR1-3 bound by betaKlotho and increase glucose uptake in adipocytes expressing FGFR1. Additionally, both FGF19 and FGF21 bind to the betaKlotho-FGFR4 complex; however, only FGF19 signals efficiently through FGFR4. Accordingly, FGF19, but not FGF21, activates FGF signaling in hepatocytes that primarily express FGFR4 and reduces transcription of CYP7A1 that encodes the rate-limiting enzyme for bile acid synthesis. We conclude that the expression of betaKlotho, in combination with particular FGFR isoforms, determines the tissue-specific metabolic activities of FGF19 and FGF21.
Klotho is an anti-aging protein with different functions of the full-length membrane protein and the secreted hormone-like form. Using overexpression and knock-down approaches as well as embryonic fibroblasts of knock-out mice we present evidence that Klotho is shedded by the alpha-secretases ADAM10 and 17 as well as by the beta-secretase beta-APP cleaving enzyme 1. The remaining membrane-bound fragment is a substrate for regulated intramembrane proteolysis by gamma-secretase. Our data suggest that therapeutic approaches targeting these proteases should be carefully analyzed for potential side effects on Klotho-mediated physiological processes.
Klotho, a key aging regulator, is predominantly expressed in the kidney. Various methods now enable the measurement of soluble αKlotho blood levels in humans. Limited studies have explored the renal origin of circulating αKlotho in humans. Soluble αKlotho in the inferior vena cava blood was measured using an enzyme-linked immunosorbent assay kit using blood samples from patients undergoing adrenal venous catheterization for close examination of primary aldosteronism. The concentration at the suprarenal inferior vena cava (476 ± 68.2) was significantly higher than that at the infrarenal inferior vena cava (434 ± 74.8) (p = 0.018), with a rate of change of 8.12 (2.3)%. We demonstrate a step-up in αKlotho concentration from the infrarenal to suprarenal vena cava in humans, supporting the kidney's origin of soluble αKlotho in the bloodstream. Klotho, un regulador clave del envejecimiento, se expresa predominantemente en el riñón. En la actualidad, diversos métodos permiten medir el nivel sanguíneo de α-klotho soluble en humanos. Son escasos los estudios que han explorado el origen renal de la α-klotho circulante en humanos. Se midió la α-klotho soluble en la sangre de la vena cava inferior mediante un kit de ensayo inmunoabsorbente ligado a enzimas en muestras de sangre de pacientes con cateterismo venoso suprarrenal para un examen detallado del aldosteronismo primario. La concentración en la vena cava inferior suprarrenal (476 ± 68,2) fue significativamente superior a la de la vena cava inferior infrarrenal (434 ± 74,8) (p = 0,018), con una tasa de variación del 8,12% (2,3%). Demostramos un aumento de la concentración de α-klotho desde la vena cava infrarrenal a la suprarrenal en humanos, lo que respalda el origen renal de α-klotho soluble en el torrente sanguíneo.
