Klotho, an important new factor for the activity of Ca2+ channels, connecting calcium homeostasis, ageing and uraemia.

In human ageing, changes in calcium distribution take place. The calcium content in bone tissue diminishes and extraskeletal calcifications, especially vascular calcifications, occur. Recent research has documented the fact that the vascular calcification process is regulated [1,2] and that this process is accelerated in uraemia [3]. Multiple factors have been proposed to influence the process of ageing. An interrelationship between sex hormones and calcium homeostasis is well established [4]. In the last decade, a new hormone, klotho, has emerged as an important player in the ageing process [5,6], and a connection between klotho and the kidneys has been proposed [7,8]. Furthermore, a recent article in ‘Science’ by Chang et al. [9] links klotho to calcium homeostasis. Calcium has important extracellular as well as intracellular functions. Its extracellular functions include a role in blood clotting, maintenance of plasma membrane integrity and intercellular adhesion. Extracellular calcium provides a source of Ca2þ, essential for intracellular processes. Furthermore, extracellular calcium provides a constant supply to the exchange of calcium within the skeleton, which represents the largest compartment of total body calcium, containing more than 99%. Intracellular calcium is an important intracellular second messenger regulating multiple cellular functions, such as metabolism, motility, secretion and proliferation. It is a cofactor for several intracellular enzymes, e.g. mitochondrial dehydrogenases, various phospholipases and proteases [10,11]. The free extracellular Ca2þ concentration is maintained within a narrow range [12]. The traditional model of overall calcium homeostasis has two key components. The first comprises several distinct cell types that sense changes in extracellular Ca2þ leading to appropriate changes in the secretion of the calciotropic hormones, parathyroid hormone (PTH), 1,25(OH)2D and calcitonin [13,10]. The second key component is the effector systems, specialized calcium-translocating cells of the kidneys, bones and intestine, that respond to the calciotropic hormones. In Ca2þ-translocating epithelial cells in the distal tubule and proximal intestine, the active Ca2þ absorption is a three-step process, consisting of passive entry of Ca2þ across the luminal or apical membrane, diffusion of Ca2þ through the cytosol, where the Ca2þ is buffered by calcium-binding proteins (calbindin-D28K and calbindin-D9K), and active extrusion of Ca2þ across the basolateral membrane by the Naþ/Ca2þ-exchanger in the kidneys and the plasma membrane Ca2þ-ATPase in the kidneys and intestine [14]. Until recently, the mechanism by which Ca2þ enters the translocating epithelia was unknown. A major breakthrough came with the identification of an epithelial Ca2þ channel family consisting of two members of the transient receptor potential (TRP) superfamily, TRPV5 and TRPV6 [15]. TRPV5 is localized predominantly at the luminal membrane of the distal convoluted tubule and connecting tubule in the kidneys. TRPV6 is localized in the brush border membrane of the duodenum. Both channels are permeable for monovalent and divalent cations with a high selectivity for Ca2þ. At the transcriptional level, TRPV5 and TRPV6 are controlled by 1,25(OH)2D3, and independent of vitamin D by dietary calcium and oestrogen [16–19]. The finding that oestrogen regulates the expression of calcium channels might contribute further to understanding the pathogenesis of a negative calcium balance in ageing and post-menopausal women. TRPV5 and TRPV6 are constitutively active. Correspondence and offprint request to: Klaus Olgaard, Nephrological Departments P, Rigshospitalet, Copenhagen, Denmark. Email: [email protected] Nephrol Dial Transplant (2006) 21: 1770–1772