New Insights into the Mechanism of Action of Soluble Klotho

Dalton, George D.; Xie, Jingyuan; An, Sung Wan; Huang, Chou Long

doi:10.3389/fendo.2017.00323

Cited by 145 publications

(119 citation statements)

References 129 publications

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“…This hypothesis is consistent with the fact that Klotho orthologs in Caenorhabditis elegans encode only KL1 domain-like proteins that inhibit DAF-2, which is homologous to IGF-1 signaling in mammals (13). Additional studies found that sKL inhibits TNF-α, IGF-1, Wnt, and TGF-β signaling (1,(14)(15)(16)(17)(18). In addition, sKL is proposed to bind to gangliosides containing α-2-3-sialyllactose in lipid rafts to inhibit PI3K signaling (19), as well as regulate calcium-permeable transient receptor potential canonical type isoform 6 (TRPC6) channels (20).…”

Section: Introductionsupporting

confidence: 80%

FGF23 expression is stimulated in transgenic α-Klotho longevity mouse model

Xiao¹,

King²,

Mancarella³

et al. 2019

JCI Insight

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Section: Introductionsupporting

confidence: 80%

FGF23 expression is stimulated in transgenic α-Klotho longevity mouse model

Xiao¹,

King²,

Mancarella³

et al. 2019

JCI Insight

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“…Klotho was originally identified as an aging suppressor gene that includes α-, β-, and γ-Klotho based on their predicted primary sequences [4]. Among these variants, α-Klotho has been widely studied in the kidney and heart and their related complications.…”

Section: Introductionmentioning

confidence: 99%

Serum Klotho, Cardiovascular Events, and Mortality in Nondiabetic Chronic Kidney Disease

Yang

et al. 2020

Cardiorenal Med

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Background: Experimental studies indicate that Klotho deficiency is a pathogenic factor for CKD-related complications, including cardiovascular disease (CVD). However, the association between serum Klotho and clinical outcomes in nondiabetic CKD patients needs to be further clarified. We aimed to determine whether serum Klotho levels are associated with CVD events and mortality in predialysis CKD patients without diabetes. Methods: A total of 336 CKD stage 2-5 predialysis patients without diabetes were recruited and followed from the end of 2014 to January 2019 for CVD events and overall mortality. Serum Klotho was detected by ELISA and divided into quartiles (lowest, middle, second highest, and highest quartiles) according to their serum Klotho category. Results: After a median follow-up of 3.52 years (IQR 3.34-3.76), Kaplan-Meier analysis showed that, compared to participants with a Klotho level in the highest quartile (the reference category), those in the lowest Klotho quartile were associated with a higher all-cause mortality risk (HR = 7.05; 95% CI 1.59-31.25) and a higher CVD event risk (HR = 3.02; 95% CI 1.45-6.30). In addition, the middle Klotho quartile was also associated with CVD event risk (HR = 2.56; 95% CI 1.21-5.41). Moreover, in the multivariate-adjusted model, the lowest Klotho quartile remained significantly associated with all-cause mortality (HR = 5.17; 95% CI 1.07-24.96), and the middle Klotho quartile maintained a significant association with CVD event risk (HR = 2.32; 95% CI 1.03-5.21). Conclusion: These results suggest that lower serum Klotho levels are independently associated with overall mortality and CVD events in nondiabetic predialysis CKD patients.

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“…Klotho is a membrane protein, and a soluble form of this protein is identified in the blood, cerebral fluid and urine, presumably exhibiting pleiotropic actions [55]. Klotho was originally identified as an anti-aging protein mainly expressed in renal tubule epithelial cells [56].…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Roles of Matrilin-2 and Klotho in Modulating the Inflammatory Activity of Human Aortic Valve Cells

Yao

Zhang

Zhai

et al. 2020

Cells

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Background: Calcific aortic valve disease (CAVD) is a chronic inflammatory disease. Soluble extracellular matrix (ECM) proteins can act as damage-associated molecular patterns and may induce valvular inflammation. Matrilin-2 is an ECM protein and has been found to elevate the pro-osteogenic activity in human aortic valve interstitial cells (AVICs). Klotho, an anti-aging protein, appears to have anti-inflammatory properties. The effect of matrilin-2 and Klotho on AVIC inflammatory responses remains unclear. Methods and Results: Isolated human AVICs were exposed to matrilin-2. Soluble matrilin-2 induced the production of ICAM-1, MCP-1, and IL-6. It also induced protein kinase R (PKR) activation via Toll-like receptor (TLR) 2 and 4. Pretreatment with PKR inhibitors inhibited NF-κB activation and inflammatory mediator production induced by matrilin-2. Further, recombinant Klotho suppressed PKR and NF-κB activation and markedly reduced the production of inflammatory mediators in human AVICs exposed to matrilin-2. Conclusions: This study revealed that soluble matrilin-2 upregulates AVIC inflammatory activity via activation of the TLR-PKR-NF-κB pathway and that Klotho is potent to suppress AVIC inflammatory responses to a soluble ECM protein through inhibiting PKR. These novel findings indicate that soluble matrilin-2 may accelerate the progression of CAVD by inducing valvular inflammation and that Klotho has the potential to suppress valvular inflammation.

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New Insights into the Mechanism of Action of Soluble Klotho

Cited by 145 publications

References 129 publications

FGF23 expression is stimulated in transgenic α-Klotho longevity mouse model

FGF23 expression is stimulated in transgenic α-Klotho longevity mouse model

Serum Klotho, Cardiovascular Events, and Mortality in Nondiabetic Chronic Kidney Disease

Mechanistic Roles of Matrilin-2 and Klotho in Modulating the Inflammatory Activity of Human Aortic Valve Cells

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