The secreted Klotho protein restores phosphate retention and suppresses accelerated aging in Klotho mutant mice

Chen, Tso Hsiao; Kuro‐o, Makoto; Chen, Cheng Hsien; Sue, Yuh Mou; Chen, Yen Cheng; Wu, Ho Han; Cheng, Chung Yi

doi:10.1016/j.ejphar.2012.09.032

Cited by 87 publications

(74 citation statements)

References 35 publications

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“…The phosphaturic effect of injected soluble aKlotho is fully intact in the FGF23 2/2 mouse and in cultured cells in the complete absence of FGF23. 21 Further support of the endocrine action of circulating aKlotho is the fact that the systemic administration of recombinant Klotho protein 26,27 or viral delivery of aKlotho 28 can rescue a multitude of the phenotypic features of genetic aKlotho deficiency in different organ systems. 26,29 The kidney has the highest level of expression of aKlotho, but it is important to know whether aKlotho circulating in serum is derived from the kidney.…”

mentioning

confidence: 99%

“…21 Further support of the endocrine action of circulating aKlotho is the fact that the systemic administration of recombinant Klotho protein 26,27 or viral delivery of aKlotho 28 can rescue a multitude of the phenotypic features of genetic aKlotho deficiency in different organ systems. 26,29 The kidney has the highest level of expression of aKlotho, but it is important to know whether aKlotho circulating in serum is derived from the kidney. Serum aKlotho levels in patients with CKD are extremely variable [30][31][32][33][34][35][36][37][38][39] probably due to assay-related variance.…”

mentioning

confidence: 99%

“…Understanding the source and clearance of Klotho is critical because restoration of aKlotho in deficient states reverses the phenotype, 2,26,43 which has great therapeutic potential. 2,26,43 We show that the kidney is the principal contributor to circulating aKlotho and simultaneously, is also the major organ where circulating aKlotho is taken up from the circulation. Thus kidney disease is expected to affect both production and clearance of aKlotho in a complex fashion.…”

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confidence: 99%

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Renal Production, Uptake, and Handling of Circulating αKlotho

Shi

Zhang³

et al. 2016

Journal of the American Society of Nephrology

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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.

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Renal Production, Uptake, and Handling of Circulating αKlotho

Shi

Zhang³

et al. 2016

Journal of the American Society of Nephrology

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“…Both m-KL and soluble forms have been reported to inhibit canonical Wnt signaling by interfering with the interactions between Wnt ligands and their receptors (Liu et al, 2007;Sun et al, 2015). Suggesting that this is relevant to the brain, p-KL represses Wnt signaling in oligodendrocyte cell models (Chen et al, 2013a;Chen et al, 2013b), and the suppression of this pathway has been shown by others to promote oligodendrocyte differentiation (Guo et al, 2015). However, Wnt inhibition is highly unlikely to be the only mechanism by which brain α-Klotho signals.…”

Section: What Does Brain α-Klotho Do?mentioning

confidence: 99%

“…These studies have reported that recombinant p-KL promotes the differentiation and myelination of a human oligodendrocytic hybrid cell line (Chen et al, 2015a), and the maturation of rat oligodendrocytes in vitro (Chen et al, 2013a), via the coordinate regulation of several key signaling pathways including Wnt, NFκB, p53, Akt and ERK. Since kl/kl hypomorphic mice display decreased myelination (Chen et al, 2013b) and mice over-expressing α-Klotho display enhanced remyelination after cuprizone-induced demyelination (Zeldich et al, 2015), the control of myelination seems a likely physiological role for brain α-Klotho.…”

Section: Effects Of α-Klotho On Neural Cells In Vitromentioning

confidence: 99%

The relevance of α-KLOTHO to the central nervous system: Some key questions

Cararo-Lopes

Mazucanti

Scavone

et al. 2017

Ageing Research Reviews

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Mechanisms and Regulation of Intestinal Phosphate Absorption

Hernando¹,

Wagner²

2018

Comprehensive Physiology

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States of hypo- and hyperphosphatemia have deleterious consequences including rickets/osteomalacia and renal/cardiovascular disease, respectively. Therefore, the maintenance of appropriate plasma levels of phosphate is an essential requirement for health. This control is executed by the collaborative action of intestine and kidney whose capacities to (re)absorb phosphate are regulated by a number of hormonal and metabolic factors, among them parathyroid hormone, fibroblast growth factor 23, 1,25(OH) vitamin D , and dietary phosphate. The molecular mechanisms responsible for the transepithelial transport of phosphate across enterocytes are only partially understood. Indeed, whereas renal reabsorption entirely relies on well-characterized active transport mechanisms of phosphate across the renal proximal epithelia, intestinal absorption proceeds via active and passive mechanisms, with the molecular identity of the passive component still unknown. The active absorption of phosphate depends mostly on the activity and expression of the sodium-dependent phosphate cotransporter NaPi-IIb (SLC34A2), which is highly regulated by many of the factors, mentioned earlier. Physiologically, the contribution of NaPi-IIb to the maintenance of phosphate balance appears to be mostly relevant during periods of low phosphate availability. Therefore, its role in individuals living in industrialized societies with high phosphate intake is probably less relevant. Importantly, small increases in plasma phosphate, even within normal range, associate with higher risk of cardiovascular disease. Therefore, therapeutic approaches to treat hyperphosphatemia, including dietary phosphate restriction and phosphate binders, aim at reducing intestinal absorption. Here we review the current state of research in the field. © 2017 American Physiological Society. Compr Physiol 8:1065-1090, 2018.

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The secreted Klotho protein restores phosphate retention and suppresses accelerated aging in Klotho mutant mice

Cited by 87 publications

References 35 publications

Renal Production, Uptake, and Handling of Circulating αKlotho

Renal Production, Uptake, and Handling of Circulating αKlotho

The relevance of α-KLOTHO to the central nervous system: Some key questions

Mechanisms and Regulation of Intestinal Phosphate Absorption

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