Establishment of the Anti-Klotho Monoclonal Antibodies and Detection of Klotho Protein in Kidneys

Kato, Yukinari; Arakawa, Emi; Kinoshita, Shigeyoshi; Shirai, Akio; Furuya, Akiko; Yamano, Kazuya; Nakamura, Kazuyasu; Iida, Akihiro; Anazawa, Hideharu; Koh, Naoki; Iwano, Akiko; Imura, Akihiro; Fujimori, Toshihiko; Kuro‐o, Makoto; Hanai, Nobuo; Takeshige, Kazuhiko; Nabeshima, Yo Ichi

doi:10.1006/bbrc.1999.2009

Cited by 148 publications

(123 citation statements)

References 9 publications

(12 reference statements)

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“…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

346

297

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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.

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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

346

297

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“…The antibody used for the analysis is directed against the intracellular domain of the membranal form of klotho. Human kidney sections, which are known to express high klotho levels only at distal tubules (Kato et al, 2000), served as controls (Figure 1a). Higher klotho expression was noted in all normal breast samples and in 90% of the normal breast samples adjacent to invasive ductal carcinoma or DCIS, compared with only 17% in DCIS and 22% invasive ductal carcinoma (Po0.0001, Figure 1, Table 1a).…”

Section: Reduced Klotho Expression In Breast Cancermentioning

confidence: 99%

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

et al. 2008

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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.

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“…Immunohistochemistry was performed with the anti-Klotho monoclonal antibody KM2119. 10 For staining parathyroid hormone (PTH), anti-PTH rabbit anti-serum (Biogenesis) was used.…”

Section: Histochemistrymentioning

confidence: 99%

“…The Klotho protein level in kidneys was examined by Western blots. 10 The protein amount in the heterozygous kl…”

Section: Generation Of Klotho-null Mice With a Lacz Reporter Gene Systemmentioning

confidence: 99%

Sinoatrial Node Dysfunction and Early Unexpected Death of Mice With a Defect of klotho Gene Expression

Takeshita¹,

Fujimori²,

Kurotaki³

et al. 2004

Circulation

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196

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Background-Homozygous mutant mice with a defect of klotho gene expression (kl/kl) show multiple age-related disorders and premature death from unknown causes. Methods and Results-The kl/kl mice subjected to 20-hour restraint stress showed a high rate (20/30) of sudden death, which was associated with sinoatrial node dysfunction (conduction block or arrest). Heart rate and plasma norepinephrine of kl/kl mice, unlike those of wild-type (WT) mice, failed to increase during the stress. Intrinsic heart rate after pharmacological blockade of autonomic nerves in kl/kl mice was significantly lower than that in WT mice (380Ϯ33 versus 470Ϯ44 bpm; nϭ7). The sinus node recovery time after an overdrive pacing (600 bpm, 30 seconds) in kl/kl mice was significantly longer than in WT mice (392Ϯ37 versus 233Ϯ24 ms; nϭ6). In isolated sinoatrial node preparations, the positive chronotropic effect of isoproterenol was significantly less, whereas the negative chronotropic effect of acetylcholine was significantly greater in kl/kl than in WT mice. There was no degenerative structural change in the sinoatrial node of kl/kl mice. The precise localization of klotho was analyzed in newly prepared klotho-null mice with a reporter gene system (kl Ϫgeo ). Homozygous kl Ϫgeo mice showed characteristic age-associated phenotypes that were almost identical to those of kl/kl mice. In the kl Ϫgeo mice, klotho expression was recognized exclusively in the sinoatrial node region in the heart in addition to parathyroid, kidney, and choroid plexus. Conclusions-In the heart, klotho is expressed solely at the sinoatrial node. klotho gene expression is essential for the sinoatrial node to function as a dependable pacemaker under conditions of stress.

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Establishment of the Anti-Klotho Monoclonal Antibodies and Detection of Klotho Protein in Kidneys

Cited by 148 publications

References 9 publications

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

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

Sinoatrial Node Dysfunction and Early Unexpected Death of Mice With a Defect of klotho Gene Expression

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