Role of SGK1 in the Osteogenic Transdifferentiation and Calcification of Vascular Smooth Muscle Cells Promoted by Hyperglycemic Conditions

Poetsch, Florian; Henze, Laura A.; Estepa, Misael; Moser, Barbara; Pieske, Burkert; Läng, Florian; Eckardt, Kai‐Uwe; Alesutan, Ioana; Voelkl, Jakob

doi:10.3390/ijms21197207

Cited by 24 publications

(33 citation statements)

References 65 publications

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“…SGK1 is typically expressed at low levels, but up-regulated during various pathological conditions [ 58 ]. Accordingly, SGK1 is up-regulated in VSMCs during pro-calcifying conditions [ 8 ] and SGK1 is required for triggering pro-calcific signaling during high phosphate, high glucose or interleukin-18 exposure [ 8 , 43 , 59 ]. SGK1 activates the transcription factor NF-κB to mediate at least some of its pro-calcific effects [ 8 ], but the signaling events upstream of SGK1 were ill-defined.…”

Section: Discussionmentioning

confidence: 99%

Acid sphingomyelinase promotes SGK1-dependent vascular calcification

et al. 2021

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In chronic kidney disease (CKD), hyperphosphatemia is a key factor promoting medial vascular calcification, a common complication associated with cardiovascular events and high mortality. Vascular calcification involves osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs), but the complex signaling events inducing pro-calcific pathways are incompletely understood. The present study investigated the role of acid sphingomyelinase (ASM)/ceramide as regulator of VSMC calcification. In vitro, both, bacterial sphingomyelinase and phosphate increased ceramide levels in VSMCs. Bacterial sphingomyelinase as well as ceramide supplementation stimulated osteo-/chondrogenic transdifferentiation during control and high phosphate conditions and augmented phosphate-induced calcification of VSMCs. Silencing of serum- and glucocorticoid-inducible kinase 1 (SGK1) blunted the pro-calcific effects of bacterial sphingomyelinase or ceramide. Asm deficiency blunted vascular calcification in a cholecalciferol-overload mouse model and ex vivo isolated-perfused arteries. In addition, Asm deficiency suppressed phosphate-induced osteo-/chondrogenic signaling and calcification of cultured VSMCs. Treatment with the functional ASM inhibitors amitriptyline or fendiline strongly blunted pro-calcific signaling pathways in vitro and in vivo. In conclusion, ASM/ceramide is a critical upstream regulator of vascular calcification, at least partly, through SGK1-dependent signaling. Thus, ASM inhibition by repurposing functional ASM inhibitors to reduce the progression of vascular calcification during CKD warrants further study.

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Section: Discussionmentioning

confidence: 99%

Acid sphingomyelinase promotes SGK1-dependent vascular calcification

et al. 2021

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“…These cells contribute to the creation of a pro-calcific environment in the media of the vasculature and actively promote tissue mineralization [9]. Hyperglycemia has been suggested to be a key pathological factor that triggers the expression of osteogenic markers in VSMCs [12][13][14] and augments vascular calcification [12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

“…The reprogramming of VSMCs is controlled by complex intracellular signaling pathways [9,16,17]. A key mediator of the pro-calcific effects of high glucose in VSMCs is the transcription factor NF-kB (nuclear factor kappa-light-chain-enhancer of activated Bcells) [14,18]. High levels of glucose activate NF-kB in VSMCs [14,19,20].…”

Section: Introductionmentioning

confidence: 99%

“…A key mediator of the pro-calcific effects of high glucose in VSMCs is the transcription factor NF-kB (nuclear factor kappa-light-chain-enhancer of activated Bcells) [14,18]. High levels of glucose activate NF-kB in VSMCs [14,19,20]. Interference with NF-kB activation can suppress high glucose-induced osteogenic signaling in VSMCs [14].…”

Section: Introductionmentioning

confidence: 99%

“…High levels of glucose activate NF-kB in VSMCs [14,19,20]. Interference with NF-kB activation can suppress high glucose-induced osteogenic signaling in VSMCs [14]. Zinc may act as an inhibitor of NF-kB activity in VSMCs [21].…”

Section: Introductionmentioning

confidence: 99%

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Zinc Ameliorates the Osteogenic Effects of High Glucose in Vascular Smooth Muscle Cells

Henze

Estepa

Pieske

et al. 2021

Cells

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In diabetic patients, medial vascular calcification is common and associated with increased cardiovascular mortality. Excessive glucose concentrations can activate the nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-kB) and trigger pro-calcific effects in vascular smooth muscle cells (VSMCs), which may actively augment vascular calcification. Zinc is able to mitigate phosphate-induced VSMC calcification. Reduced serum zinc levels have been reported in diabetes mellitus. Therefore, in this study the effects of zinc supplementation were investigated in primary human aortic VSMCs exposed to excessive glucose concentrations. Zinc treatment was found to abrogate the stimulating effects of high glucose on VSMC calcification. Furthermore, zinc was found to blunt the increased expression of osteogenic and chondrogenic markers in high glucose-treated VSMCs. High glucose exposure was shown to activate NF-kB in VSMCs, an effect that was blunted by additional zinc treatment. Zinc was further found to increase the expression of TNFα-induced protein 3 (TNFAIP3) in high glucose-treated VSMCs. The silencing of TNFAIP3 was shown to abolish the protective effects of zinc on high glucose-induced NF-kB-dependent transcriptional activation, osteogenic marker expression, and the calcification of VSMCs. Silencing of the zinc-sensing receptor G protein-coupled receptor 39 (GPR39) was shown to abolish zinc-induced TNFAIP3 expression and the effects of zinc on high glucose-induced osteogenic marker expression. These observations indicate that zinc may be a protective factor during vascular calcification in hyperglycemic conditions.

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Naphthenic acid fraction components from oil sands process‐affected water from the Athabasca Oil Sands Region impair murine osteoblast differentiation and function

Gutgesell

Jamshed

Frank

et al. 2022

J of Applied Toxicology

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The extraction of bitumen from surface mining in the Athabasca Oil Sands Region (AOSR) produces large quantities of oil sands process‐affected water (OSPW) that needs to be stored in settling basins near extraction sites. Chemical constituents of OSPW are known to impair bone health in some organisms, which can lead to increased fracture risk and lower reproductive fitness. Naphthenic acid fraction components (NAFCs) are thought to be among the most toxic class of compounds in OSPW; however, the effect of NAFCs on osteoblast development is largely unknown. In this study, we demonstrate that NAFCs from OSPW inhibit osteoblast differentiation and deposition of extracellular matrix, which is required for bone formation. Extracellular matrix deposition was inhibited in osteoblasts exposed to 12.5–125 mg/L of NAFC for 21 days. We also show that components within NAFCs inhibit the expression of gene markers of osteoblast differentiation and function, namely, alkaline phosphatase (Alp), osteocalcin, and collagen type 1 alpha 1 (Col1a1). These effects were partially mediated by the induction of glucocorticoid receptor (GR) activity; NAFC induces the expression of the GR activity marker genes Sgk1 (12.5 mg/L) and p85a (125 mg/L) and inhibits GR protein (125 mg/L) and Opg RNA (12.5 mg/L) expression. This study provides evidence that NAFC concentrations of 12.5 mg/L and above can directly act on osteoblasts to inhibit bone formation and suggests that NAFCs contain components that can act as GR agonists, which may have further endocrine disrupting effects on exposed wildlife.

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Role of SGK1 in the Osteogenic Transdifferentiation and Calcification of Vascular Smooth Muscle Cells Promoted by Hyperglycemic Conditions

Cited by 24 publications

References 65 publications

Acid sphingomyelinase promotes SGK1-dependent vascular calcification

Acid sphingomyelinase promotes SGK1-dependent vascular calcification

Zinc Ameliorates the Osteogenic Effects of High Glucose in Vascular Smooth Muscle Cells

Naphthenic acid fraction components from oil sands process‐affected water from the Athabasca Oil Sands Region impair murine osteoblast differentiation and function

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