Klotho: a novel regulator of calcium and phosphorus homeostasis

Huang, Chou Long; Moe, Orson W.

doi:10.1007/s00424-011-0950-5

Cited by 68 publications

(45 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Since aKlotho functions as an enzyme, 13,21,54 it can theoretically modify the glycans and hence reduce the negative charge barrier of the GBM with resultant leak of aKlotho into urine. To exclude that, we treated fresh normal kidney slices with aKlotho, glucuronidase, or sialidase, and examined their effects on negative charge.…”

Section: Distribution Of Exogenous Aklotho Protein In the Kidneymentioning

confidence: 99%

“…1,5,6,10 aKlotho expression is restricted to a few organs including the kidney, 1 parathyroid glands, 11 and sinoatrial node 12 where it forms tetrameric complexes with FGFR1c, 3c, or 4 (2Klotho:2FGFR), and serves as the high-affinity receptor for circulating FGF23 to regulate mineral metabolism. 4,[13][14][15] bKlotho is expressed in the liver and fat and forms complexes with FGFR1c or 4 to support FGF15/19 and FGF21 signaling. bKlotho is involved in regulation of caloric homeostasis and bile secretion.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Renal Production, Uptake, and Handling of Circulating αKlotho

Shi

Zhang³

et al. 2016

Journal of the American Society of Nephrology

Self Cite

228

254

View full text Add to dashboard Cite

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.

show abstract

Section: Distribution Of Exogenous Aklotho Protein In the Kidneymentioning

confidence: 99%

mentioning

confidence: 99%

Renal Production, Uptake, and Handling of Circulating αKlotho

Shi

Zhang³

et al. 2016

Journal of the American Society of Nephrology

Self Cite

228

254

View full text Add to dashboard Cite

show abstract

“…The ectodomain (soluble klotho, sKL) is released into the systemic circulation, urine, and cerebrospinal fluid and functions as a humoral factor (2,5). To date, more than 10 different functions of sKL have been described (2,(6)(7)(8)(9). sKL regulates ion transporters, antagonizes Wnt and TGF-β1signaling to suppress cellular senescence, tissue fibrosis, and cancer metastasis, and inhibits insulin and insulin-like growth factor-1 (IGF1)-driven PI3K/Akt signaling contributing to extension of lifespan in mice, cardioprotection, and inhibition of tumor cell proliferation.…”

mentioning

confidence: 99%

Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling

Dalton

Al-Juboori

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Soluble klotho, the shed ectodomain of the antiaging membrane protein α-klotho, is a pleiotropic endocrine/paracrine factor with no known receptors and poorly understood mechanism of action. Soluble klotho down-regulates growth factor-driven PI3K signaling, contributing to extension of lifespan, cardioprotection, and tumor inhibition. Here we show that soluble klotho binds membrane lipid rafts. Klotho binding to rafts alters lipid organization, decreases membrane's propensity to form large ordered domains for endocytosis, and down-regulates raft-dependent PI3K/Akt signaling. We identify α2-3-sialyllactose present in the glycan of monosialogangliosides as targets of soluble klotho. α2-3-Sialyllactose is a common motif of glycans. To explain why klotho preferentially targets lipid rafts we show that clustering of gangliosides in lipid rafts is important. In vivo, raft-dependent PI3K signaling is up-regulated in klotho-deficient mouse hearts vs. wild-type hearts. Our results identify ganglioside-enriched lipid rafts to be receptors that mediate soluble klotho regulation of PI3K signaling. Targeting sialic acids may be a general mechanism for pleiotropic actions of soluble klotho.soluble klotho | lipid rafts | gangliosides | sialic acids | TRPC6 M ice homozygous for a severe hypomorphic α-klotho allele manifest multiple aging-related phenotypes and die prematurely at 2-3 mo after birth (1). α-Klotho is predominantly expressed in renal tubules, parathyroid glands, and epithelial cells of the choroids plexus, but not in myocardium. Overexpression of α-klotho extends life span in mice, indicating that it is an agingsuppression molecule (2). The full-length α-klotho protein is a single-pass membrane protein with a large extracellular domain, a membrane-spanning segment, and a short intracellular carboxyl terminus (1). Membranous α-klotho associates with FGF receptors to form coreceptors for the ligand FGF23, a bone-derived circulating hormone that plays an important role in phosphate homeostasis (3).The ectodomain of α-klotho, ∼950 aa in length, is composed of two internal repeats, KL1 and KL2, each sharing amino acid sequence homology to family-1 glycosidases (4). The ectodomain (soluble klotho, sKL) is released into the systemic circulation, urine, and cerebrospinal fluid and functions as a humoral factor (2, 5). To date, more than 10 different functions of sKL have been described (2, 6-9). sKL regulates ion transporters, antagonizes Wnt and TGF-β1signaling to suppress cellular senescence, tissue fibrosis, and cancer metastasis, and inhibits insulin and insulin-like growth factor-1 (IGF1)-driven PI3K/Akt signaling contributing to extension of lifespan in mice, cardioprotection, and inhibition of tumor cell proliferation. A fundamental gap in the understanding of sKL's mechanism of action is the lack of knowledge of potential membrane receptor(s) that mediate cellular responses to sKL.Lipid rafts are highly dynamic, cholesterol-and sphingolipidrich membrane microdomains that compartmentalize cellular processes such as ...

show abstract

“…As mentioned above, klotho acts with FGF receptor as a coreceptor in the binding of FGF23 in DCTs for phosphate and vitamin D 3 regulation (Kurosu et al 2006). The Klotho-FGF23-FGF receptor complex in DCTs may produce putative paracrine factors on PTCs where phosphate transporters and enzymes for vitamin D 3 regulation are located (Huang and Moe 2011). The extracellular domain of Klotho is also known to be cleaved from plasma membranes, secreted to the circulatoin and present in urine (Hu et al 2011); this soluble klotho form may directly act on PTCs.…”

Section: Klothomentioning

confidence: 99%