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. and Luong, T.T. and Tuffaha, R. and Musculus, K. and Auer, T. and Lian, X. and Daniel, C. and Zickler, D. and Boehme, B. and Sacherer, M. and Metzler, B. and Kuhl, D. and Gollasch, M. and Amann, K. and Müller, D.N. and Pieske, B. and 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
ISSN:	0021-9738
Publisher:	American Society for Clinical Investigation
Volume:	128
Number:	7
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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