α-Klotho and kidney function decline: An important step forward in understanding the link between mineral metabolism and kidney disease progression

摘要

Ever since its discovery about 15 years ago, a-klotho has captured a great deal of attention in cardiovascular and kidney research. First proposed as an antiaging factor because of its beneficial effects on a number of aging-related phenotypes in animals, subsequent studies showed that a-klotho has pleotro-pic actions, including the regulation of mineral homeo-stasis, glucose trafficking, and endothelial function. These actions are carried out by the 2 main forms of a-klotho, a membrane-bound form and a circulating form. The former consists of a single transmembrane domain with an extracellular domain that has 2 internal repeats, whereas the latter is derived from either alternative RNA splicing or, more commonly, proteo-lytic cleavage of the extracellular domain (Fig 1). The transmembrane form of a-klotho functions as the critical cofactor that allows fibroblast growth factor 23 (FGF-23) to bind to its cognate receptor with an affinity high enough to effect signal transduction in the kidney and parathyroid glands.