Fig. 1.

Source of soluble Klotho. The kidney is the main source of circulating Klotho under physiological conditions. Both renal proximal and distal tubules express membrane Klotho protein and also presumably produce secreted Klotho protein through alternative splicing. The secreted Klotho only contains a Kl1 domain and is directly secreted into the blood circulation (left panel); its biological function is not completely clear yet. Extracellular domain of membrane Klotho containing Kl1 and Kl2 repeats is shed and cleaved by secretases into either full extracellular domain or Kl1 repeat, and directly exerts its biological actions. Both cleaved Klotho fragments are in the blood circulation (right panel).