Klotho in chronic kidney disease--what's new?

Klotho, named after a Greek goddess who spins the thread of life, was identified in 1997 as a gene mutated in a mouse strain that developed a premature ageing syndrome [1]. A defect in Klotho gene expression in mice results in shortened life span, growth retardation, hypogonadism, accelerated thymic involution, skin atrophy, muscle atrophy, vascular calcification, osteopaenia, pulmonary emphysema, cognition impairment [2], hearing loss [3] and motor neuron degeneration [4] among others. These ageing-like phenotypes are associated with elevated serum levels of 1,25-dihydroxyvitamin D3, phosphate and calcium [5]. The Klotho gene encodes a single-pass transmembrane protein that belongs to a family 1 glycosidase [6] and is expressed primarily in renal tubules. Function of the Klotho protein was not clear at that time. Fibroblast growth factor-23 (FGF23) was cloned based on sequence similarity to the other members of FGF ligand superfamily [7] and identified in 2000 as a gene mutated in patients with autosomal dominant hypophosphataemic rickets (ADHR) [8]. Unlike classical FGF ligands that function as paracrine and/or autocrine factors, FGF23 functions as an endocrine factor [9]. FGF23 is primarily produced in osteocytes and acts on the kidney to induce phosphate excretion (phosphaturic hormone) and suppress serum levels of 1,25-dihydroxyvitamin D3 (counter-regulatory hormone for vitamin D) [10]. Patients with ADHR exhibit increased serum FGF23 levels due to mutations in the FGF23 gene that confer resistance to proteolytic degeneration of FGF23 protein [11]. However, the identity of the FGF23 receptor was not clear because the affinity of FGF23 to any known FGF receptors is extremely low in vitro [12]. Klotho and FGF23, seemingly unrelated proteins, had been studied independently until it was realized that Klothodeficient mice [1] and FGF23-deficient mice [13] shared identical phenotypes. FGF23-deficient mice also develop multiple ageing-like phenotypes associated with hyperphosphataemia, hypercalcaemia and hypervitaminosis D. We reported in 2006 that Klotho formed a complex with several FGF receptor isoforms (FGFR1c, 3c, 4) and significantly increased the affinity of FGF23 to the FGF receptors [14]. Thus, Klotho functions as an obligatory coreceptor for FGF23. This finding was later confirmed in an independent study [15]. The fact that FGF23 requires Klotho as a co-receptor explains why Klotho-deficient mice develop phenotypes identical with those observed in FGF23-deficient mice and why Klotho-deficient mice had extremely high serum FGF23 levels [15]. In addition, kidney-specific expression of Klotho explains why FGF23 can identify the kidney as its target organ among many other tissues that express multiple FGFR isoforms.