Kuro-O Makoto
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9072, USA.
Kidney Int Suppl. 2011 Apr;79(121):S20-3. doi: 10.1038/ki.2011.26. Epub 2011 Feb 23.
Klotho is a putative aging suppressor gene encoding a single-pass transmembrane co-receptor that makes the fibroblast growth factor (FGF) receptor specific for FGF-23. In addition to multiple endocrine organs, Klotho is expressed in kidney distal convoluted tubules and parathyroid cells, mediating the role of FGF-23 in bone-kidney-parathyroid control of phosphate and calcium. Klotho⁻/⁻ mice display premature aging and chronic kidney disease-associated mineral and bone disorder (CKD-MBD)-like phenotypes mediated by hyperphosphatemia and remediated by phosphate-lowering interventions (diets low in phosphate or vitamin D; knockouts of 1α-hydroxylase, vitamin D receptor, or NaPi cotransporter). CKD can be seen as a state of hyperphosphatemia-induced accelerated aging associated with Klotho deficiency. Humans with CKD experience decreased Klotho expression as early as stage 1 CKD; Klotho continues to decline as CKD progresses, causing FGF-23 resistance and provoking large FGF-23 and parathyroid hormone increases, and hypovitaminosis D. Secreted Klotho protein, formed by extracellular clipping, exerts FGF-23-independent phosphaturic and calcium-conserving effects through its paracrine action on the proximal and distal tubules, respectively. We contend that decreased Klotho expression is the earliest biomarker of CKD and the initiator of CKD-MBD pathophysiology. Maintaining normal phosphate levels with phosphate binders in patients with CKD with declining Klotho expression is expected to reduce mineral and vascular derangements.
klotho是一种假定的衰老抑制基因，编码一种单次跨膜共受体，该共受体使成纤维细胞生长因子（FGF）受体对FGF-23具有特异性。除多个内分泌器官外，klotho还在肾远曲小管和甲状旁腺细胞中表达，介导FGF-23在骨-肾-甲状旁腺对磷酸盐和钙的调控中的作用。Klotho基因敲除小鼠表现出早衰和慢性肾脏病相关的矿物质和骨代谢紊乱（CKD-MBD）样表型，这些表型由高磷血症介导，并可通过降低磷酸盐的干预措施（低磷或低维生素D饮食；敲除1α-羟化酶、维生素D受体或钠磷共转运体）得到改善。CKD可被视为一种由高磷血症诱导的、与klotho缺乏相关的加速衰老状态。CKD患者早在1期CKD时就出现klotho表达下降；随着CKD的进展，klotho持续下降，导致FGF-23抵抗，并引起FGF-23和甲状旁腺激素大幅升高以及维生素D缺乏。通过细胞外剪切形成的分泌型klotho蛋白分别通过对近端和远端小管的旁分泌作用发挥不依赖FGF-23的促尿磷排泄和保钙作用。我们认为，klotho表达下降是CKD最早的生物标志物，也是CKD-MBD病理生理学的启动因素。对于klotho表达下降的CKD患者，使用磷结合剂维持正常的磷酸盐水平有望减少矿物质和血管紊乱。
