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Titel
SGK1-dependent stimulation of vascular smooth muscle cell osteo-/chondrogenic transdifferentiation by interleukin-18
AutorInnenVoelkl, Jakob ; Alesutan, Ioana
Erschienen in
The Journal of Clinical Investigation, 2018, Jg. 128, H. 7, S. 3024-3040
ErschienenThe American Society for Clinical Investigation, 2018
SpracheEnglisch
DokumenttypAufsatz in einer Zeitschrift
Schlagwörter (EN)Cell Biology / Vascular Biology / Cardiovascular disease / Chronic kidney disease / NF-kappaB
URNurn:nbn:at:at-ubl:3-298 Persistent Identifier (URN)
DOI10.1172/JCI96477 
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 Das Werk ist gemäß den "Hinweisen für BenützerInnen" verfügbar
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SGK1-dependent stimulation of vascular smooth muscle cell osteo-/chondrogenic transdifferentiation by interleukin-18 [13.39 mb]
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Zusammenfassung (Englisch)

Medial vascular calcification, associated with enhanced mortality in chronic kidney disease (CKD), is fostered by osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Here, we describe that serum- and glucocorticoid-inducible kinase 1 (SGK1) was upregulated in VSMCs under calcifying conditions. In primary human aortic VSMCs, overexpression of constitutively active SGK1S422D, but not inactive SGK1K127N, upregulated osteo-/chondrogenic marker expression and activity, effects pointing to increased osteo-/chondrogenic transdifferentiation. SGK1S422D induced nuclear translocation and increased transcriptional activity of NF-B. Silencing or pharmacological inhibition of IKK abrogated the osteoinductive effects of SGK1S422D. Genetic deficiency, silencing, and pharmacological inhibition of SGK1 dissipated phosphate-induced calcification and osteo-/chondrogenic transdifferentiation of VSMCs. Aortic calcification, stiffness, and osteo-/chondrogenic transdifferentiation in mice following cholecalciferol overload were strongly reduced by genetic knockout or pharmacological inhibition of Sgk1 by EMD638683. Similarly, Sgk1 deficiency blunted vascular calcification in apolipoprotein Edeficient mice after subtotal nephrectomy. Treatment of human aortic smooth muscle cells with serum from uremic patients induced osteo-/chondrogenic transdifferentiation, effects ameliorated by EMD638683. These observations identified SGK1 as a key regulator of vascular calcification. SGK1 promoted vascular calcification, at least partly, via NF-B activation. Inhibition of SGK1 may, thus, reduce the burden of vascular calcification in CKD.

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CC-BY-Lizenz (4.0)Creative Commons Namensnennung 4.0 International Lizenz