期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 128, 期 7, 页码 3024-3040出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI96477
关键词
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资金
- Berlin Institute of Health Translational Postdoc Grant
- Deutsche Forschungsgemeinschaft [AL2054/1-1, VO2259/2-1, GO766/12-3, GO766/22-1]
- Sonnenfeld Foundation
- Else Kroner-Fresenius-Stiftung
- European Union Seventh Framework Programme [FP7/2007-2013-603288-Sys-Vasc]
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-kappa 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 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-kappa B activation. Inhibition of SGK1 may, thus, reduce the burden of vascular calcification in CKD.
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