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<lom:identifier>
  
<lom:catalog>DOI</lom:catalog>

  
<lom:entry>
  
<lom:langstring xml:lang="x-none">10.1016/j.kint.2024.07.011</lom:langstring>

  
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</lom:identifier>

  
<lom:title>
  
<lom:langstring xml:lang="en">Augmentative effects of leukemia inhibitory factor reveal a critical role for TYK2 signaling in vascular calcification</lom:langstring>

  
</lom:title>

  
<lom:description>
  
<lom:langstring xml:lang="en">Medial vascular calcification in chronic kidney disease (CKD) involves pro-inflammatory pathways induced by hyperphosphatemia. Several interleukin 6 family members have been associated with pro-calcific effects in vascular smooth muscle cells (VSMCs) and are considered as therapeutic targets. Therefore, we investigated the role of leukemia inhibitory factor (LIF) during VSMC calcification. LIF expression was found to be increased following phosphate exposure of VSMCs. LIF supplementation aggravated, while silencing of endogenous LIF or LIF receptor (LIFR) ameliorated the pro-calcific effects of phosphate in VSMCs. The soluble LIFR mediated antagonistic effects towards LIF and reduced VSMC calcification. Mechanistically, LIF induced phosphorylation of the non-receptor tyrosine-protein kinase 2 (TYK2) and signal transducer and activator of transcription-3 (STAT3) in VSMCs. TYK2 inhibition by deucravacitinib, a selective, allosteric oral immunosuppressant used in psoriasis treatment, not only blunted the effects of LIF, but also interfered with the pro-calcific effects induced by phosphate. Conversely, TYK2 overexpression aggravated VSMC calcification. Ex vivo calcification of mouse aortic rings was ameliorated by Tyk2 pharmacological inhibition and genetic deficiency. Cholecalciferol-induced vascular calcification in mice was improved by Tyk2 inhibition and in the Tyk2-deficient mice. Similarly, calcification was ameliorated in Abcc6/Tyk2-deficient mice after adenine/high phosphorus-induced CKD. Thus, our observations indicate a role for LIF in CKD-associated vascular calcification. Hence, the effects of LIF identify a central pro-calcific role of TYK2 signaling, which may be a future target to reduce the burden of vascular calcification in CKD.</lom:langstring>

  
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<lom:language>eng</lom:language>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">Chronic Kidney Disease; Leukemia Inhibitory Factor; STAT3; TYK2; Vascular Calcification; Vascular Smooth Muscle Cells</lom:langstring>

  
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<lom:datetime>2024-11-06T13:53:45.320Z</lom:datetime>

  
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N:Alesutan;Ioana;
FN:Ioana Alesutan
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N:Voelkl;Jakob;
FN:Jakob Voelkl
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N:Eckardt;Kai-Uwe;
FN:Kai-Uwe Eckardt
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N:Vlahou;Antonia;
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<lom:vcard>BEGIN:VCARD
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N:Müller;Mathias;
FN:Mathias Müller
X-ORCID:https://orcid.org/0000-0002-7879-3552
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N:Bielesz;Bernhard;
FN:Bernhard Bielesz
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N:Antlanger;Marlies;
FN:Marlies Antlanger
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N:Suessner;Susanne;
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N:Cejka;Daniel;
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N:Pasch;Andreas;
FN:Andreas Pasch
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N:Gollmann-Tepeköylü;Can;
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N:Makridakis;Manousos;
FN:Manousos Makridakis
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N:Deisl;Christine;
FN:Christine Deisl
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N:Schuchardt;Mirjam;
FN:Mirjam Schuchardt
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<lom:vcard>BEGIN:VCARD
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N:Zickler;Daniel;
FN:Daniel Zickler
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<lom:vcard>BEGIN:VCARD
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N:Mitter;Gregor;
FN:Gregor Mitter
END:VCARD</lom:vcard>

  
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<lom:vcard>BEGIN:VCARD
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N:Henze;Laura A.;
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N:Pitigala;Lakmi;
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N:Estepa;Misael;
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N:Razazian;Mehdi;
FN:Mehdi Razazian
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N:Luong;Trang T. D.;
FN:Trang T. D. Luong
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