Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Voelkl, J; Luong, TT; Tuffaha, R; Musculus, K; Auer, T; Lian, X; Daniel, C; Zickler, D; Boehme, B; Sacherer, M; Metzler, B; Kuhl, D; Gollasch, M; Amann, K; Müller, DN; Pieske, B; Lang, F; Alesutan, I.
SGK1 induces vascular smooth muscle cell calcification through NF-κB signaling.
J Clin Invest. 2018; 128(7):3024-3040
Doi: 10.1172/JCI96477
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- Co-Autor*innen der Med Uni Graz
- Pieske Burkert Mathias
- Sacherer Michael
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- Abstract:
- 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-κB. 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 E-deficient 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-κB activation. Inhibition of SGK1 may, thus, reduce the burden of vascular calcification in CKD.
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- Cells, Cultured - administration & dosage
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- Protein Kinase Inhibitors - pharmacology
- Protein Serine-Threonine Kinases - deficiency, genetics, metabolism
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- Vascular Calcification - etiology, metabolism, pathology