Renal Production, Uptake, and Handling of Circulating αKlotho

Abstract

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

Xeno-Klotho Inhibits Parathyroid Hormone Signaling

“…(21) In analogy, the kidney is a major source of circulating klotho. (3,4,6) Renal interstitial klotho concentrations could exceed the levels in circulation, reaching effective concentrations to interact with PTH receptors expressed on proximal tubules. The present data demonstrate that klotho directly interacts with the PTH receptor to inhibit the binding of PTH and suggest that klotho acts as a messenger of FGF23 signaling to suppress vitamin D activation.…”

Human alternative Klotho mRNA is a nonsense-mediated mRNA decay target inefficiently spliced in renal disease

“…Because depletion of circulating Klotho levels is found after bilateral nephrectomy (38) and after kidney-specific deletion of Klotho (32), the kidney has been identified as principal contributor to systemic Klotho levels, adding to the relevance of our findings in renal cells and tissues. Caution, however, should be exercised in extrapolating our secreted Klotho results to other tissues.…”

“…An experiment performed by Hu et al is in line with cleaved Klotho as the sole contributor to circulating Klotho; Hu et al show that inhibition of both α-and β-secretases for 48 hours in mice virtually depletes circulating Klotho (38).…”

Study of Serum Soluble Klotho in Egyptian Hemodialysis Patients

“…The vascular smooth muscle also appears to be Klotho-deficient in patients with CKD [13] . The kidney is a major source of circulating sKlotho as demonstrated by 30% to 50% decreases after nephrectomy in living donors in humans without deteriorated renal function [14] , and also recently in animal studies [15] . Moreover, recent demonstrations of Klotho expression in vascular tissue highlight the vascular territory as another source of sKlotho [10] .…”