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SGK1 induces vascular smooth muscle cell calcification through NF-[kappa]B signaling
- Source :
- Journal of Clinical Investigation. July, 2018, Vol. 128 Issue 7, p3024, 17 p.
- Publication Year :
- 2018
-
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 [SGK1.sup.S422D], but not inactive [SGK1.sup.K127N], upregulated osteo-/chondrogenic marker expression and activity, effects pointing to increased osteo-/chondrogenic transdifferentiation. [SGK1.sup.S422D] induced nuclear translocation and increased transcriptional activity of NF-[kappa]B. Silencing or pharmacological inhibition of IKK abrogated the osteoinductive effects of [SGK1.sup.S422D]. 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.<br />Introduction Medial vascular calcification is associated with cardiovascular events and mortality (1) of patients with chronic kidney disease (CKD) (2). In contrast to intimal atherosclerosis, vascular calcification is fostered by [...]
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 128
- Issue :
- 7
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.547075418
- Full Text :
- https://doi.org/10.1172/JCI96477