Renal Production, Uptake, and Handling of Circulating αKlotho

[摘要] α Klotho is a multifunctional protein highly expressed in the kidney. Soluble α Klotho is released through cleavage of the extracellular domain from membrane α Klotho by secretases to function as an endocrine/paracrine substance. The role of the kidney in circulating α Klotho production and handling is incompletely understood, however. Here, we found higher α Klotho concentration in suprarenal compared with infrarenal inferior vena cava in both rats and humans. In rats, serum α Klotho concentration dropped precipitously after bilateral nephrectomy or upon treatment with inhibitors of α Klotho extracellular domain shedding. Furthermore, the serum half-life of exogenous α Klotho in anephric rats was four- to five-fold longer than that in normal rats, and exogenously injected labeled recombinant α 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 α 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 α Klotho homeostasis, producing and releasing α Klotho into the circulation and clearing α Klotho from the blood into the urinary lumen.

[学科分类] 泌尿医学