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

Voelkl J, Luong TTD, Tuffaha R, Musculus K, Auer T, Lian X, Daniel C, Zickler D, Boehme B, Sacherer M, Metzler B, Kuhl D, Gollasch M, Amann KU, Mueller DN, Pieske B, Lang F, Alesutan I (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Journal of Clinical Investigation American Society for Clinical Investigation

DOI: 10.1172/JCI96477

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.

Authors with CRIS profile

Christoph Daniel Department of Nephropathology Kerstin Ute Amann Professur für Nephropathologie

Involved external institutions

Charité - Universitätsmedizin Berlin DE Germany (DE) Eberhard Karls Universität Tübingen DE Germany (DE) Medizinische Universität Innsbruck AT Austria (AT) Universitätsklinikum Hamburg-Eppendorf (UKE) DE Germany (DE) Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK e.V.) DE Germany (DE)

How to cite

APA:

Voelkl, J., Luong, T.T.D., Tuffaha, R., Musculus, K., Auer, T., Lian, X.,... Alesutan, I. (2018). SGK1 induces vascular smooth muscle cell calcification through NF-κB signaling. Journal of Clinical Investigation. https://dx.doi.org/10.1172/JCI96477

MLA:

Voelkl, Jakob, et al. "SGK1 induces vascular smooth muscle cell calcification through NF-κB signaling." Journal of Clinical Investigation (2018).

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