Basic ResearchRenal Production, Uptake, and Handling of Circulating αKlothoHu, Ming Chang*,†; Shi, Mingjun†; Zhang, Jianning*; Addo, Tayo*; Cho, Han Ju†; Barker, Sarah L.‡; Ravikumar, Priya*,†; Gillings, Nancy†; Bian, Ao†; Sidhu, Sachdev S.‡; Kuro-o, Makoto†,‖,§; Moe, Orson W.*,†,¶ Author Information Departments of *Internal Medicine, ¶Physiology, and ‖Pathology, †Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas; ‡Banting and Best Department of Medical Research and Department of Molecular Genetics, The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada; and §Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan Present address: Dr. Ao Bian, Department of Internal Medicine, Division of Nephrology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China. Correspondence: Dr. Ming Chang Hu or Dr. Orson W. Moe, Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8885. Email [email protected] or [email protected] Received October 23, 2014 Accepted March 14, 2015 Journal of the American Society of Nephrology 27(1):p 79-90, January 2016. | DOI: 10.1681/ASN.2014101030 Buy Metrics Abstract αKlotho is a multifunctional protein highly expressed in the kidney. Soluble αKlotho is released through cleavage of the extracellular domain from membrane αKlotho by secretases to function as an endocrine/paracrine substance. The role of the kidney in circulating αKlotho production and handling is incompletely understood, however. Here, we found higher αKlotho concentration in suprarenal compared with infrarenal inferior vena cava in both rats and humans. In rats, serum αKlotho concentration dropped precipitously after bilateral nephrectomy or upon treatment with inhibitors of αKlotho extracellular domain shedding. Furthermore, the serum half-life of exogenous αKlotho in anephric rats was four- to five-fold longer than that in normal rats, and exogenously injected labeled recombinant αKlotho was detected in the kidney and in urine of rats. Both in vivo (micropuncture) and in vitro (proximal tubule cell line) studies showed that αKlotho traffics from the basal to the apical side of the proximal tubule via transcytosis. Thus, we conclude that the kidney has dual roles in αKlotho homeostasis, producing and releasing αKlotho into the circulation and clearing αKlotho from the blood into the urinary lumen. Copyright © 2016 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.