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Renal Production, Uptake, and Handling of Circulating alphaKlotho #MMPMID25977312
Hu MC; Shi M; Zhang J; Addo T; Cho HJ; Barker SL; Ravikumar P; Gillings N; Bian A; Sidhu SS; Kuro-o M; Moe OW
J Am Soc Nephrol 2016[Jan]; 27 (1): 79-90 PMID25977312show ga
alphaKlotho is a multifunctional protein highly expressed in the kidney. Soluble alphaKlotho is released through cleavage of the extracellular domain from membrane alphaKlotho by secretases to function as an endocrine/paracrine substance. The role of the kidney in circulating alphaKlotho production and handling is incompletely understood, however. Here, we found higher alphaKlotho concentration in suprarenal compared with infrarenal inferior vena cava in both rats and humans. In rats, serum alphaKlotho concentration dropped precipitously after bilateral nephrectomy or upon treatment with inhibitors of alphaKlotho extracellular domain shedding. Furthermore, the serum half-life of exogenous alphaKlotho in anephric rats was four- to five-fold longer than that in normal rats, and exogenously injected labeled recombinant alphaKlotho was detected in the kidney and in urine of rats. Both in vivo (micropuncture) and in vitro (proximal tubule cell line) studies showed that alphaKlotho traffics from the basal to the apical side of the proximal tubule via transcytosis. Thus, we conclude that the kidney has dual roles in alphaKlotho homeostasis, producing and releasing alphaKlotho into the circulation and clearing alphaKlotho from the blood into the urinary lumen.
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J+Am+Soc+Nephrol 2016 ; 27 (1): 79-90
