The klotho gene (KL) was first identified as a putative aging-suppressor gene that extended lifespan when over-expressed, and accelerated aging-like phenotypes when disrupted in mice. It encodes a single-pass transmembrane protein and is expressed predominantly in kidney, where it functions as an obligate co-receptor for fibroblast growth factor 23 (FGF-23). FGF-23 is a bone-derived hormone that suppresses phosphate reabsorption and 1,25 dihydroxyvitamin D3 (vitamin D) synthesis in the kidney. Klotho is also expressed in the parathyroid gland, where FGF-23 decreases expression and secretion of parathyroid hormone, further suppressing vitamin D synthesis in kidney. Thus, FGF-23 functions as a phosphaturic hormone as well as a counter-regulatory hormone for vitamin D, thereby inducing negative phosphate balance. Mice lacking either FGF-23 or klotho exhibit hyperphosphatemia in addition to developing multiple aging-like phenotypes, which can be rescued by resolving phosphate retention. These findings have unveiled an unexpected link between aging and phosphate. In patients with chronic kidney disease (CKD), phosphate retention is universally seen and has been associated with increased mortality risk. CKD patients exhibit high serum FGF23 levels together with reduced klotho expression in the kidney and parathyroid, rendering FGF23 and klotho as potential biomarkers and therapeutic targets for CKD. The klotho protein serves not only as a co-receptor for FGF23 but also functions as a humoral factor. Klotho’s extracellular domain is released into blood and urine by ectodomain shedding and exerts various functions independently of FGF23, including regulation of multiple ion channels and transporters. Decrease in urinary klotho protein levels has been identified as one of the earliest biomarkers of CKD progression. This review will focus on the current understanding of klotho protein function with an emphasis on its potential involvement in the pathophysiology of CKD.
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