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SGK1 induces vascular smooth muscle cell calcification through NF-κB signaling

Item Type:Article
Title:SGK1 induces vascular smooth muscle cell calcification through NF-κB signaling
Creators Name:Voelkl, J., Luong, T.T., 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, D.N., Pieske, B., Lang, F. and Alesutan, I.
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.
Keywords:Animal Disease Models, ApoE Knockout Mice, Benzamides, Cell Transdifferentiation, Chondrogenesis, Cultured Cells, Gene Expression Regulation, Hydrazines, Immediate-Early Proteins, Inbred C57BL Mice, Knockout Mice, NF-kappa B, Osteogenesis, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Renal Insufficiency, Signal Transduction, Smooth Muscle Myocytes, Vascular Calcification, Animals, Mice
Source:Journal of Clinical Investigation
Publisher:American Society for Clinical Investigation
Page Range:3024-3040
Date:2 July 2018
Official Publication:https://doi.org/10.1172/JCI96477
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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