Renal Production, Uptake, and Handling of Circulating αKlotho

alpha Klotho is a multifunctional protein highly expressed in the kidney. Soluble alpha Klotho is released through cleavage of the extracellular domain from membrane alpha Klotho by secretases to function as an endocrine/paracrine substance. The role of the kidney in circulating alpha Klotho production and handling is incompletely understood, however. Here, we found higher alpha Klotho concentration in suprarenal compared with infrarenal inferior vena cava in both rats and humans. In rats, serum alpha Klotho concentration dropped precipitously after bilateral nephrectomy or upon treatment with inhibitors of alpha Klotho extracellular domain shedding. Furthermore, the serum half-life of exogenous alpha Klotho in anephric rats was four-to five-fold longer than that in normal rats, and exogenously injected labeled recombinant alpha Klotho was detected in the kidney and in urine of rats. Both in vivo (micropuncture) and in vitro (proximal tubule cell line) studies showed that alpha Klotho traffics from the basal to the apical side of the proximal tubule via transcytosis. Thus, we conclude that the kidney has dual roles in alpha Klotho homeostasis, producing and releasing alpha Klotho into the circulation and clearing alpha Klotho from the blood into the urinary lumen.