ArticleAging cell2016
Deficiency in the anti-aging gene Klotho promotes aortic valve fibrosis through AMPKα-mediated activation of RUNX2.
Article in Aging cell, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 50 citations in OpenAlex.
- Uremic toxin p‑cresyl sulfate enhances the calcification of aortic valvular interstitial cells via klotho/sirtuin‑1 signaling.Molecular medicine reports · 2026Article
- Considerations in the Use of Mouse Models of Vascular and Valvular Calcification.Arteriosclerosis, thrombosis, and vascular biology · 2026Review
- Fibulin 2 Deficiency Drives Epigenetic Hypertension.Hypertension (Dallas, Tex. : 1979) · 2026Article
- Valvular calcification in chronic kidney disease: new insights from recent clinical and preclinical studies.Clinical kidney journal · 2025Article
- Diabetes and calcific aortic valve disease: implications of glucose-lowering medication as potential therapy.Frontiers in pharmacology · 2025Review
- Runt-related transcription factors: from pathogenesis to therapeutic targets in multiple-organ fibrosis.Frontiers in cell and developmental biology · 2025Review
- "A Friend Among Strangers" or the Ambiguous Roles of Runx2.Biomolecules · 2024Review
- Molecular Interplay in Cardiac Fibrosis: Exploring the Functions of RUNX2, BMP2, and Notch.Reviews in cardiovascular medicine · 2024Review
- Identification and Validation of the miR/RAS/RUNX2 Autophagy Regulatory Network in AngII-Induced Hypertensive Nephropathy in MPC5 Cells Treated with Hydrogen Sulfide Donors.Antioxidants (Basel, Switzerland) · 2024Article
- KDM6A Demethylase Regulates Renal Sodium Excretion and Blood Pressure.Hypertension (Dallas, Tex. : 1979) · 2024Article
- Loss of SLC27A5 Activates Hepatic Stellate Cells and Promotes Liver Fibrosis via Unconjugated Cholic Acid.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Parishin alleviates vascular ageing in mice by upregulation of Klotho.Journal of cellular and molecular medicine · 2023Article
- Inhibition of miR-101-3p prevents human aortic valve interstitial cell calcification through regulation of CDH11/SOX9 expression.Molecular medicine (Cambridge, Mass.) · 2023Article
- Aging impairs arterial compliance via Klotho-mediated downregulation of B-cell population and IgG levels.Cellular and molecular life sciences : CMLS · 2022Article
- In Vivo Cardiac-specific Expression of Adenylyl Cyclase 4 Gene Protects against Klotho Deficiency-induced Heart Failure.Translational research : the journal of laboratory and clinical medicine · 2022Article
- Calcific aortic valve disease: from molecular and cellular mechanisms to medical therapy.European heart journal · 2022Article
- Administration of α-Klotho Does Not Rescue Renal Anemia in Mice.Frontiers in pediatrics · 2022Article
- Increased TGFβ1 and SMAD3 Contribute to Age-Related Aortic Valve Calcification.Frontiers in cardiovascular medicine · 2022Article
- α-Klotho released from HK-2 cells inhibits osteogenic differentiation of renal interstitial fibroblasts by inactivating the Wnt-β-catenin pathway.Cellular and molecular life sciences : CMLS · 2021Article
- Estrogen inhibits renal Na-Pi Co-transporters and improves klotho deficiency-induced acute heart failure.Redox biology · 2021Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Fibrotic aortic valve disease (FAVD) is an important cause of aortic stenosis, yet currently there is no effective treatment for FAVD due to its unknown etiology. The purpose of this study was to investigate whether deficiency in the anti-aging Klotho gene (KL) promotes high-fat-diet-induced FAVD and to explore the underlying molecular mechanism. Heterozygous Klotho-deficient (KL(+/-) ) mice and WT littermates were fed with a high-fat diet (HFD) or normal diet for 13 weeks, followed by treatment with the AMPKα activator (AICAR) for an additional 2 weeks. A HFD caused a greater increase in collagen levels in the aortic valves of KL(+/-) mice than of WT mice, indicating that Klotho deficiency promotes HFD-induced aortic valve fibrosis (AVF). AMPKα activity (pAMPKα) was decreased, while protein expression of collagen I and RUNX2 was increased in the aortic valves of KL(+/-) mice fed with a HFD. Treatment with AICAR markedly attenuated HFD-induced AVF in KL(+/-) mice. AICAR not only abolished the downregulation of pAMPKα but also eliminated the upregulation of collagen I and RUNX2 in the aortic valves of KL(+/-) mice fed with HFD. In cultured porcine aortic valve interstitial cells, Klotho-deficient serum plus cholesterol increased RUNX2 and collagen I protein expression, which were attenuated by activation of AMPKα by AICAR. Interestingly, silencing of RUNX2 abolished the stimulatory effect of Klotho deficiency on cholesterol-induced upregulation of matrix proteins, including collagen I and osteocalcin. In conclusion, Klotho gene deficiency promotes HFD-induced fibrosis in aortic valves, likely through the AMPKα-RUNX2 pathway.
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