Molecular Cloning of RatklothocDNA: Markedly Decreased Expression ofklothoby Acute Inflammatory Stress

Ohyama, Yoshio; Kurabayashi, Masahiko; Masuda, Hiroaki; Nakamura, Toshio; Aihara, Yasushi; Kaname, Tadashi; Suga, Tatsuo; Arai, M.; Aizawa, Hiroki; Matsumura, Yutaka; Kuro‐o, Makoto; Nabeshima, Yo Ichi; Nagail, Ryozo

doi:10.1006/bbrc.1998.9576

Cited by 137 publications

(153 citation statements)

References 11 publications

Supporting

Mentioning

135

Contrasting

Unclassified

Order By: Relevance

“…aKlotho is found in urine and serum of rodents and humans 2,20,42,56 ; and the kidney has the highest abundance of aKlotho compared with other organs. Clinical and experimental animal studies showed low renal tubular aKlotho expression in both acute kidney injury and CKD 10,40,42,43,[56][57][58][59][60][61][62] and low circulating aKlotho levels in kidney diseases of a variety of etiologies in animals 42,43,56,62 and humans. 32,44,61,63 These data suggest that the kidney contributes to circulating aKlotho.…”

Section: Discussionmentioning

confidence: 99%

“…4,[7][8][9] aKlotho is a type-I single-pass transmembrane protein with a long extracellular region harboring b-glucosidase-like motifs called Kl domains. 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.…”

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

210

225

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: Discussionmentioning

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

210

225

View full text Add to dashboard Cite

show abstract

“…40 The kidney is the main site of Klotho expression, and kidney injury, as corroborated by our findings, results in reduced renal Klotho expression. 25,41 We may speculate that a decreased renal expression of Klotho may have local and systemic adverse consequences. Regarding potential systemic effects, reduced kidney Klotho expression during AKI persisted beyond recovery of renal function and was associated with decreased circulating Klotho.…”

Section: Discussionmentioning

confidence: 99%

The Inflammatory Cytokines TWEAK and TNFα Reduce Renal Klotho Expression through NFκB

Moreno

Izquierdo²,

Sanchez-Niño³

et al. 2011

Journal of the American Society of Nephrology

336

291

View full text Add to dashboard Cite

Proinflammatory cytokines contribute to renal injury, but the downstream effectors within kidney cells are not well understood. One candidate effector is Klotho, a protein expressed by renal cells that has antiaging properties; Klotho-deficient mice have an accelerated aging-like phenotype, including vascular injury and renal injury. Whether proinflammatory cytokines, such as TNF and TNF-like weak inducer of apoptosis (TWEAK), modulate Klotho is unknown. In mice, exogenous administration of TWEAK decreased expression of Klotho in the kidney. In the setting of acute kidney injury induced by folic acid, the blockade or absence of TWEAK abrogated the injury-related decrease in renal and plasma Klotho levels. TWEAK, TNF␣, and siRNA-mediated knockdown of IB␣ all activated NFB and reduced Klotho expression in the MCT tubular cell line. Furthermore, inhibition of NFB with parthenolide prevented TWEAK-or TNF␣-induced downregulation of Klotho. Inhibition of histone deacetylase reversed TWEAKinduced downregulation of Klotho, and chromatin immunoprecipitation showed that TWEAK promotes RelA binding to the Klotho promoter, inducing its deacetylation. In conclusion, inflammatory cytokines, such as TWEAK and TNF␣, downregulate Klotho expression through an NFB-dependent mechanism. These results may partially explain the relationship between inflammation and diseases characterized by accelerated aging of organs, including CKD.

show abstract

“…It has been shown recently that A desintegrin and metalloproteinase 10 and 17 participate in this process in response to insulin stimulation (Chen et al, 2007). mRNA expression analysis identified klotho mainly in the distal renal tubules and the choroid plexus in the brain, and also in sex-hormone-responsive tissues including the placenta, testes and ovaries (Kuro-o et al, 1997;Ohyama et al, 1998;Shiraki-Iida et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer

et al. 2008

View full text Add to dashboard Cite

Klotho is an anti-aging gene, which has been shown to inhibit the insulin and insulin-like growth factor 1 (IGF-1) pathways in mice hepatocytes and myocytes. As IGF-1 and insulin regulate proliferation, survival and metastasis of breast cancer, we studied klotho expression and activities in human breast cancer. Immunohistochemistry analysis of klotho expression in breast tissue arrays revealed high klotho expression in normal breast samples, but very low expression in breast cancer. In cancer samples, high klotho expression was associated with smaller tumor size and reduced KI67 staining. Forced expression of klotho reduced proliferation of MCF-7 and MDA-MB-231 breast cancer cells, whereas klotho silencing in MCF-7 cells, which normally express klotho, enhanced proliferation. Moreover, forced expression of klotho in these cells, or treatment with soluble klotho, inhibited the activation of IGF-1 and insulin pathways, and induced upregulation of the transcription factor CCAAT/enhancer-binding protein b, a breast cancer growth inhibitor that is negatively regulated by the IGF-1-AKT axis. Co-immunoprecipitation revealed an interaction between klotho and the IGF-1 receptor. Klotho is also a known modulator of the fibroblast growth factor (FGF) pathway, a pathway that inhibits proliferation of breast cancer cells. Studies in breast cancer cells revealed increased activation of the FGF pathway by basic FGF following klotho overexpression. Klotho did not affect activation of the epidermal growth factor pathway in breast cancer cells. These data suggest klotho as a potential tumor suppressor and identify it as an inhibitor of the IGF-1 pathway and activator of the FGF pathway in human breast cancer.

show abstract

Molecular Cloning of RatklothocDNA: Markedly Decreased Expression ofklothoby Acute Inflammatory Stress

Cited by 137 publications

References 11 publications

Renal Production, Uptake, and Handling of Circulating αKlotho

Renal Production, Uptake, and Handling of Circulating αKlotho

The Inflammatory Cytokines TWEAK and TNFα Reduce Renal Klotho Expression through NFκB

Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer

Contact Info

Product

Resources

About