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Cited by 461

The DOI matches its Crossref record; 47 of the 47 references it cites were found in a registry or an index.

Vascular Klotho Deficiency Potentiates the Development of Human Artery Calcification and Mediates Resistance to Fibroblast Growth Factor 23

Open access
Lim, Kenneth, Lu, Tzong-Shi, Molostvov, Guerman, Lee, Christina, Lam, F.T., Zehnder, Daniel, Hsiao, Li-Li·2012·Circulation
DOI 10.1161/circulationaha.111.053405
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Abstract

Background—: Klotho is known to function as a cofactor for the phosphatonin, fibroblast growth factor (FGF)-23 at the kidney. FGF-23 levels rise in chronic kidney disease (CKD) despite progression of accelerated vascular calcification. There are currently conflicting data on whether FGF-23 may exhibit direct vasculoprotective effects in CKD. Methods and Results—: In this study, we describe for the first time endogenous Klotho expression in human arteries and human aortic smooth muscle cells. We show that CKD is a state of vascular Klotho deficiency promoted by chronic circulating stress factors, including proinflammatory, uremic, and disordered metabolic conditions. Mechanistic studies demonstrated that Klotho knockdown potentiated the development of accelerated calcification through a Runx2 and myocardin-serum response factor–dependent pathway. Klotho knockdown studies further revealed that vascular cells are a Klotho-dependent target tissue for FGF-23. FGF-23 mediated cellular activation of p-ERK, p-AKT, and cellular proliferative effects, which were abrogated following Klotho knockdown. We next showed that vascular Klotho deficiency driven by procalcific stressors could be restored by vitamin D receptor activators, in vitro and further confirmed using human arterial organ cultures from CKD patients, in vivo. Furthermore, restoration of suppressed Klotho expression by vitamin D receptor activators conferred human aortic smooth muscle cells responsive to FGF-23 signaling and unmasked potential anticalcific effects. Conclusions—: Chronic metabolic stress factors found in CKD promote vascular Klotho deficiency. Mechanistic studies revealed a bifunctional role for local vascular Klotho, first, as an endogenous inhibitor of vascular calcification and, second, as a cofactor required for vascular FGF-23 signaling. Furthermore, vitamin D receptor activators can restore Klotho expression and unmask FGF-23 anticalcific effects.

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Metadata

Authors
Lim, K., Lu, T.-S., Molostvov, G., Lee, C., Lam, F. T., Zehnder, D., & Hsiao, L.-L.
Venue
Circulation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2012-05-08
Volume
125
Issue
18
Pages
2243-2255
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
DOI
10.1161/circulationaha.111.053405
OpenAlex
W1976544899
Cited by
461
References
47
FWCI
38.83
Type
journal article
Language
en
Open access
bronze

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CoChat. (2026). Citation check: Vascular Klotho Deficiency Potentiates the Development of Human Artery Calcification and Mediates Resistance to Fibroblast Growth Factor 23. https://app.cochat.ai/papers/10.1161/circulationaha.111.053405
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Lim, K., Lu, T.-S., Molostvov, G., Lee, C., Lam, F. T., Zehnder, D., & Hsiao, L.-L. (2012). Vascular Klotho Deficiency Potentiates the Development of Human Artery Calcification and Mediates Resistance to Fibroblast Growth Factor 23. Circulation. https://doi.org/10.1161/circulationaha.111.053405

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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.