1. SGK1 induces vascular smooth muscle cell calcification through NF-[kappa]B signaling
- Author
-
Voelkl, Jakob, Luong, Trang T.D., Tuffaha, Rashad, Musculus, Katharina, Auer, Tilman, Lian, Xiaoming, Daniel, Christoph, Zickler, Daniel, Boehme, Beate, Sacherer, Michael, Metzler, Bernhard, Kuhl, Dietmar, Gollasch, Maik, Amann, Kerstin, Muller, Dominik N., Pieske, Burkert, Lang, Florian, and Alesutan, Ioana
- Subjects
Calcification (Physiology) -- Analysis ,Smooth muscle -- Health aspects ,Glucocorticoids -- Research ,Health care industry - 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., 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 [...]
- Published
- 2018
- Full Text
- View/download PDF