Renal Production, Uptake, and Handling of Circulating αklotho

Ming C Hu, Mingjun Shi, Jianning Zhang, Tayo A Addo, Han Ju Cho, Sarah L. Barker, Priya Ravikumar, Nancy Gillings, Ao Bian, Sachdev S. Sidhu, Makoto Kuro-o, Orson W Moe

Research output: Contribution to journalArticlepeer-review

189 Scopus citations


αKlotho is amultifunctional 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 tothe apical side of the proximal tubule via transcytosis. Thus, we conclude that the kidney has dual roles in αKlotho homeostasis, producing and releasingaKlotho into the circulationandclearing αKlotho fromthebloodinto the urinary lumen.

Original languageEnglish (US)
Pages (from-to)79-90
Number of pages12
JournalJournal of the American Society of Nephrology
Issue number1
StatePublished - Jan 2016

ASJC Scopus subject areas

  • Nephrology


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