The Role of Klotho Protein in Chronic Kidney Disease: Studies in Animals and Humans

The identification of Klotho gene was a major discovery as the gene encodes a protein regulating multiple functions. A defect in Klotho gene expression in mice results in a phenotype of premature aging including shortened life span, growth retardation, hypogonadism, skin and muscle atrophies, vascular calcification, cognition impairment, motor neuron degeneration and others. This phenotype is associated with phosphate balance disorders and underlines the major function of Klotho in mineral metabolism. As another 2 related paralogs were discovered (beta-Klotho, which is involved in bile acid and energy metabolism, and gamma-Klotho, with a yet to be defined function), this led to the revised naming of Klotho as alpha-Klotho. Two forms of alpha-Klotho protein have been reported: a membrane-bound and a soluble one. Membrane Klotho forms a complex with fibroblast growth factor (FGF) receptors and functions as an obligate co-receptor for the FGF-23 phosphatonin in distal tubules. The soluble form of Klotho seems to function as a humoral factor and regulates glycoproteins on the cell surface including ion channels and growth factors. There is data suggesting that soluble Klotho exerts phosphaturic effects independently of FGF-23. Circulating soluble Klotho is produced either by proteolytic cleavage of the extracellular domain of the transmembrane form by two membrane-anchored proteases (ADAM10 and ADAM17) or by alternative mRNA splicing. In animal models Klotho has been shown to exert pleiotropic actions, including cytoprotection, anti-oxidation, anti-apoptosis, protection of vasculature, promotion of angiogenesis and vascularization, inhibition of fibrogenesis and preservation of stem cells. The exact diagnostic and therapeutic role of Klotho in humans is not fully known yet. The article presents the role of Klotho in physiology and different stages of chronic kidney disease (CKD).