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

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SGK1 induces vascular smooth muscle cell calcification through NF-κB signaling. / Voelkl, Jakob; Luong, Trang Td; Tuffaha, Rashad; Musculus, Katharina; Auer, Tilman; Lian, Xiaoming; Daniel, Christoph; Zickler, Daniel; Boehme, Beate; Sacherer, Michael; Metzler, Bernhard; Kuhl, Dietmar; Gollasch, Maik; Amann, Kerstin; Müller, Dominik N; Pieske, Burkert; Lang, Florian; Alesutan, Ioana.

In: J CLIN INVEST, Vol. 128, No. 7, 02.07.2018, p. 3024-3040.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Voelkl, J, Luong, TT, Tuffaha, R, Musculus, K, Auer, T, Lian, X, Daniel, C, Zickler, D, Boehme, B, Sacherer, M, Metzler, B, Kuhl, D, Gollasch, M, Amann, K, Müller, DN, Pieske, B, Lang, F & Alesutan, I 2018, 'SGK1 induces vascular smooth muscle cell calcification through NF-κB signaling', J CLIN INVEST, vol. 128, no. 7, pp. 3024-3040. https://doi.org/10.1172/JCI96477

APA

Voelkl, J., Luong, T. T., Tuffaha, R., Musculus, K., Auer, T., Lian, X., Daniel, C., Zickler, D., Boehme, B., Sacherer, M., Metzler, B., Kuhl, D., Gollasch, M., Amann, K., Müller, D. N., Pieske, B., Lang, F., & Alesutan, I. (2018). SGK1 induces vascular smooth muscle cell calcification through NF-κB signaling. J CLIN INVEST, 128(7), 3024-3040. https://doi.org/10.1172/JCI96477

Vancouver

Voelkl J, Luong TT, Tuffaha R, Musculus K, Auer T, Lian X et al. SGK1 induces vascular smooth muscle cell calcification through NF-κB signaling. J CLIN INVEST. 2018 Jul 2;128(7):3024-3040. https://doi.org/10.1172/JCI96477

Bibtex

@article{7d50500820bf45228219c1ad1ca4aef8,
title = "SGK1 induces vascular smooth muscle cell calcification through NF-κB signaling",
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.",
keywords = "Journal Article",
author = "Jakob Voelkl and Luong, {Trang Td} and Rashad Tuffaha and Katharina Musculus and Tilman Auer and Xiaoming Lian and Christoph Daniel and Daniel Zickler and Beate Boehme and Michael Sacherer and Bernhard Metzler and Dietmar Kuhl and Maik Gollasch and Kerstin Amann and M{\"u}ller, {Dominik N} and Burkert Pieske and Florian Lang and Ioana Alesutan",
year = "2018",
month = jul,
day = "2",
doi = "10.1172/JCI96477",
language = "English",
volume = "128",
pages = "3024--3040",
journal = "J CLIN INVEST",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "7",

}

RIS

TY - JOUR

T1 - SGK1 induces vascular smooth muscle cell calcification through NF-κB signaling

AU - Voelkl, Jakob

AU - Luong, Trang Td

AU - Tuffaha, Rashad

AU - Musculus, Katharina

AU - Auer, Tilman

AU - Lian, Xiaoming

AU - Daniel, Christoph

AU - Zickler, Daniel

AU - Boehme, Beate

AU - Sacherer, Michael

AU - Metzler, Bernhard

AU - Kuhl, Dietmar

AU - Gollasch, Maik

AU - Amann, Kerstin

AU - Müller, Dominik N

AU - Pieske, Burkert

AU - Lang, Florian

AU - Alesutan, Ioana

PY - 2018/7/2

Y1 - 2018/7/2

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1172/JCI96477

DO - 10.1172/JCI96477

M3 - SCORING: Journal article

C2 - 29889103

VL - 128

SP - 3024

EP - 3040

JO - J CLIN INVEST

JF - J CLIN INVEST

SN - 0021-9738

IS - 7

ER -