Introduction: Medial vascular calcification, a risk factor for cardiovascular events and mortality in chronic kidney disease (CKD) patients, is a complex process tightly regulated by intracellular signaling pathways controlling osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs). However, the intracellular signaling involved in vascular calcification remained ill defined. The present study explored the role of serum- and glucocorticoid-inducible kinase 1 (SGK1) in vascular calcification. Methods: Experiments were performed in primary human and mouse aortic VSMCs, in human coronary arteries from CKD patients as well as in a mouse model of cholecalciferol overload and a mouse model of subtotal nephrectomy, induced surgically during isoflurane anaesthesia. Results: SGK1 expression was up-regulated in VSMCs under calcifying conditions. In human coronary arteries from hemodialysis patients, SGK1 expression was increased and localized in the calcified arterial regions as compared to control patients. Overexpression of constitutively active SGK1S422D, but not inactive SGK1K127N, increased osteo-/chondrogenic transdifferentiation of primary human aortic VSMCs. SGK1S422D induced nuclear translocation of NF-kB p65 and increased NF-kB-dependent transcriptional activity, while blockage of NF-kB activation blunted the osteoinductive effects of SGK1. Genetic deficiency, silencing and pharmacological inhibition of SGK1 suppressed phosphate-induced calcification and osteo-/chondrogenic transdifferentiation of VSMCs. In addition, aortic calcification and osteo-/chondrogenic transdifferentiation as well as vascular stiffness in mice following cholecalciferol overload was suppressed in Sgk1-deficient mice or by pharmacological inhibition of Sgk1 with EMD638683. Similarly, vascular calcification induced in ApoE-deficient mice after subtotal nephrectomy was suppressed in Sgk1-deficient mice. In primary human aortic VSMCs, uremic serum-induced osteo-/chondrogenic transdifferentiation was ameliorated by SGK1 inhibitor EMD638683. Conclusions: SGK1 is a key regulator of vascular calcification participating in the signaling that controls osteo-/chondrogenic transdifferentiation of VSMCs, effects involving NF-kB activation. Thus, inhibition of SGK1 may reduce the progression of vascular calcification in CKD.
Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCB366
Poster Communications: Serum- and glucocorticoid-inducible kinase 1 promotes vascular smooth muscle cell calcification via NF-kB
J. Voelkl1, T. Luong1, R. Tuffaha2, K. Musculus2, T. Auer2, X. Lian3, C. Daniel4, D. Zickler3, B. Boehme1, M. Sacherer5, B. Metzler6, D. Kuhl7, M. Gollasch3, K. Amann4, D. Müller8, B. Pieske1,9,10, F. Lang2, I. Alesutan1,9
1. Center for Cardiovascular Research Cardiology CVK, Charité - Universitätsmedizin Berlin, Berlin, Germany. 2. Department of Physiology I, Eberhard-Karls University, Tübingen, Germany. 3. Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany. 4. Department of Pathology, Universität Erlangen-Nürnberg, Erlangen, Germany. 5. Department of Cardiology, Medical University of Graz, Graz, Austria. 6. University Clinic of Internal Medicine III, Cardiology and Angiology, Medical University of Innsbruck, Innsbruck, Austria. 7. Institute for Molecular and Cellular Cognition, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 8. Experimental and Clinical Research Center, a joint cooperation between the Max-Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Berlin, Germany. 9. Berlin Institute of Health, Berlin, Germany. 10. Department of Cardiology, DHZB, Berlin, Germany.
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Where applicable, experiments conform with Society ethical requirements.