Renal Production, Uptake, and Handling of Circulating αKlotho

Overview

Journal J Am Soc Nephrol

Specialty Nephrology

Date 2015 May 16

PMID 25977312

Citations 139

Authors

Ming Chang Hu

Mingjun Shi

Jianning Zhang

Tayo Addo

Han Ju Cho

Sarah L Barker

Priya Ravikumar

Nancy Gillings

Ao Bian

Sachdev S Sidhu

Makoto Kuro-O

Orson W Moe

Affiliations

Soon will be listed here.

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.

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