Hu Ming Chang, Shi Mingjun, Zhang Jianning, Addo Tayo, Cho Han Ju, Barker Sarah L, Ravikumar Priya, Gillings Nancy, Bian Ao, Sidhu Sachdev S, Kuro-o Makoto, Moe Orson W
Departments of Internal Medicine, Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas;
Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas;
J Am Soc Nephrol. 2016 Jan;27(1):79-90. doi: 10.1681/ASN.2014101030. Epub 2015 May 14.
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.
α-klotho是一种在肾脏中高度表达的多功能蛋白质。可溶性α-klotho通过分泌酶从膜结合型α-klotho的细胞外结构域切割释放出来，作为一种内分泌/旁分泌物质发挥作用。然而，肾脏在循环中α-klotho产生和处理中的作用尚未完全了解。在这里，我们发现大鼠和人类的肾上腺下腔静脉中的α-klotho浓度高于肾下下腔静脉。在大鼠中，双侧肾切除术后或用α-klotho细胞外结构域脱落抑制剂治疗后，血清α-klotho浓度急剧下降。此外，无肾大鼠中外源性α-klotho的血清半衰期比正常大鼠长四到五倍，并且在大鼠的肾脏和尿液中检测到外源性注射的标记重组α-klotho。体内（微穿刺）和体外（近端肾小管细胞系）研究均表明，α-klotho通过转胞吞作用从近端肾小管的基底侧向顶端侧运输。因此，我们得出结论，肾脏在α-klotho稳态中具有双重作用，即产生并将α-klotho释放到循环中，以及将血液中的α-klotho清除到尿腔中。
