title: Renal Production, Uptake, and Handling of Circulating αKlotho.
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.
authors.affiliation: Departments of Internal Medicine, Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas; ming-chang.hu@utsouthwestern.edu orson.moe@utsouthwestern.edu.
authors.forename: Ming Chang
authors.initials: MC
authors.lastname: Hu
authors.affiliation: Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas;
authors.forename: Mingjun
authors.initials: M
authors.lastname: Shi
authors.affiliation: Departments of Internal Medicine.
authors.forename: Jianning
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Departments of Internal Medicine.
authors.forename: Tayo
authors.initials: T
authors.lastname: Addo
authors.affiliation: Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas;
authors.forename: Han Ju
authors.initials: HJ
authors.lastname: Cho
authors.affiliation: Banting and Best Department of Medical Research and Department of Molecular Genetics, The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada; and.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Barker
authors.affiliation: Departments of Internal Medicine, Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas;
authors.forename: Priya
authors.initials: P
authors.lastname: Ravikumar
authors.affiliation: Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas;
authors.forename: Nancy
authors.initials: N
authors.lastname: Gillings
authors.affiliation: Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas;
authors.forename: Ao
authors.initials: A
authors.lastname: Bian
authors.affiliation: Banting and Best Department of Medical Research and Department of Molecular Genetics, The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada; and.
authors.forename: Sachdev S
authors.initials: SS
authors.lastname: Sidhu
authors.affiliation: Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas; Pathology, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuro-o
authors.affiliation: Departments of Internal Medicine, Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas; Physiology, and ming-chang.hu@utsouthwestern.edu orson.moe@utsouthwestern.edu.
authors.forename: Orson W
authors.initials: OW
authors.lastname: Moe
mesh_terms: D000818:Animals; D005966:Glucuronidase / Q000097:blood / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D000090265:Klotho Proteins; D051381:Rats
chemical_list: D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: Cell & Transport Physiology; Nephrectomy; Transcytosis; [REMOVED HYPERLINK FIELD]Klotho; distal tubule; renal proximal tubule cell