ArticleJournal of molecular medicine (Berlin, Germany)2017
Klotho suppresses high phosphate-induced osteogenic responses in human aortic valve interstitial cells through inhibition of Sox9.
Article in Journal of molecular medicine (Berlin, Germany), 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 30 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
- Valvular calcification in chronic kidney disease: new insights from recent clinical and preclinical studies.Clinical kidney journal · 2025Article
- Molecular Interaction of Soluble Klotho with FGF23 in the Pathobiology of Aortic Valve Lesions Induced by Chronic Kidney Disease.International journal of biological sciences · 2024Article
- Cathepsin D elevates the fibrocalcific activity in human aortic valve cells through the ERK1/2-Sox9 pathway.Frontiers in cardiovascular medicine · 2024Article
- Exploring molecular profiles of calcification in aortic vascular smooth muscle cells and aortic valvular interstitial cells.Journal of molecular and cellular cardiology · 2023Article
- Myocardial fibrosis and calcification are attenuated by microRNA-129-5p targeting Asporin and Sox9 in cardiac fibroblasts.JCI insight · 2023Article
- Review
- Towards Personalized Therapy of Aortic Stenosis.Journal of personalized medicine · 2021Review
- Self-eating and Heart: The Emerging Roles of Autophagy in Calcific Aortic Valve Disease.Aging and disease · 2021Review
- miRNA Expression Profiling Uncovers a Role of miR-139-5p in Regulating the Calcification of Human Aortic Valve Interstitial Cells.Frontiers in genetics · 2021Article
- Hyperphosphatemia and Cardiovascular Disease.Frontiers in cell and developmental biology · 2021Review
- Review
- Article
- Review
- Deficiency of CCAAT/enhancer-binding protein homologous protein (CHOP) prevents diet-induced aortic valve calcification in vivo.Aging cell · 2017Article
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
Elevated level of blood phosphate (Pi) associated with chronic kidney disease (CKD) is a risk factor of aortic valve calcification. Aortic valve interstitial cells (AVICs) display osteogenic responses to high Pi although the underlying mechanism is incompletely understood. Sox9 is a pro-chondrogenic factor and may play a role in ectopic tissue calcification. Circulating and kidney levels of Klotho are reduced in patients with CKD. We hypothesized that Sox9 mediates high Pi-induced osteogenic responses in human AVICs and that Klotho inhibits the responses. Treatment of human AVICs with high Pi increased protein levels of Runt-related transcription factor 2 (Runx2) and alkaline phosphatase (ALP), and a prolonged exposure to high Pi caused calcium deposition. High Pi induced Sox9 upregulation through PKD and Akt activation. Knockdown of Sox9 essentially abolished the effect of high Pi on the osteogenic responses. Lower Klotho levels were observed in calcified aortic valve tissues. Interestingly, high Pi decreased Klotho levels in AVICs from normal valves, and treatment with recombinant Klotho markedly reduced the effect of high Pi on the levels of Sox9, Runx2, and ALP and suppressed calcium deposition. We conclude that high Pi induces human AVIC osteogenic responses through Sox9. Human AVICs express Klotho, and its levels in AVICs are modulated by high Pi and valvular calcification. Importantly, Klotho suppresses the pro-osteogenic effect of high Pi on human AVICs. These novel findings indicate that modulation of Klotho may have therapeutic potential for mitigation of valvular calcification associated with CKD. KEY MESSAGES: CAVD associated with chronic kidney disease is a significant clinical problem. High phosphate upregulates Sox9 through AKT and PKD in human AVICs. Calcified human aortic valves have lower levels of Klotho. Klotho suppresses Sox9 upregulation and intranuclear translocation. Klotho inhibits high phosphate-induced osteogenic activity in human AVICs.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.