Cooperative Signaling via Transcription Factors NF-κB and AP1/c-Fos Mediates Endothelial Cell STIM1 Expression and Hyperpermeability in Response to Endotoxin

DebRoy, Auditi; Vogel, Stephen M.; Soni, Dheeraj; Sundivakkam, Premanand; Malik, Asrar B.; Tiruppathì, Chinnaswamy

doi:10.1074/jbc.m114.570051

Cited by 54 publications

(48 citation statements)

References 53 publications

(89 reference statements)

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“…Little is known about the regulation of the abundance of STIM1, which could also affect channel function. In this regard, the transcription factor NF-B has been recently reported to promote STIM1 protein expression in mast cells and in vascular endothelial cells (7,12). In the present study, we showed that HNF4␣, a nuclear transcription factor, regulated STIM1 expression by functioning as a repressor in MCs.…”

Section: Discussionsupporting

confidence: 58%

“…Because HNF4␣ expression is tissue specific (11,23,41), our results suggest that transcription factor-regulated STIM1 expression might be cell context dependent. Indeed, we failed to observe an NF-B effect on STIM1 expression in MCs (data not shown), as previously described in mast cell and pulmonary vascular endothelial cells (7,12). HNF4␣ is generally thought as a transcriptional activator and is known to activate a wide variety of genes involved in glucose, fatty acid, cholesterol, and amino acid metabolism (18,20,31,45).…”

Section: Discussionsupporting

confidence: 56%

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Impairment of hepatic nuclear factor-4α binding to theStim1promoter contributes to high glucose-induced upregulation of STIM1 expression in glomerular mesangial cells

Wang

Chaudhari

Ren

et al. 2015

American Journal of Physiology-Renal Physiology

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Wang Y, Chaudhari S, Ren Y, Ma R. Impairment of hepatic nuclear factor 4␣ binding to the Stim1 promoter contributes to high glucoseinduced upregulation of STIM1 expression in glomerular mesangial cells. Am J Physiol Renal Physiol 308: F1135-F1145, 2015. First published March 18, 2015 doi:10.1152/ajprenal.00563.2014.-The present study was carried out to investigate if hepatic nuclear factor (HNF)4␣ contributed to the high glucose-induced increase in stromal interacting molecule (STIM)1 protein abundance in glomerular mesangial cells (MCs). Western blot and immunofluorescence experiments showed HNF4␣ expression in MCs. Knockdown of HNF4␣ using a small interfering RNA approach significantly increased mRNA expression levels of both STIM1 and Orai1 and protein expression levels of STIM1 in cultured human MCs. Consistently, overexpression of HNF4␣ reduced expressed STIM1 protein expression in human embryonic kidney-293 cells. Furthermore, high glucose treatment did not significantly change the abundance of HNF4␣ protein in MCs but significantly attenuated HNF4␣ binding activity to the Stim1 promoter. Moreover, knockdown of HNF4␣ significantly augmented store-operated Ca 2ϩ entry, which is known to be gated by STIM1 and has recently been found to be antifibrotic in MCs. In agreement with those results, knockdown of HNF4␣ significantly attenuated the fibrotic response of high glucose. These results suggest that HNF4␣ negatively regulates STIM1 transcription in MCs. High glucose increases STIM1 expression levels by impairing HNF4␣ binding activity to the Stim1 promoter, which subsequently releases Stim1 transcription from HNF4␣ repression. Since the STIM1-gated storeoperated Ca 2ϩ entry pathway in MCs has an antifibrotic effect, inhibition of HNF4␣ in MCs might be a potential therapeutic option for diabetic kidney disease. hepatic nuclear factor 4␣; stromal interacting molecule 1; storeoperated Ca 2ϩ entry; mesangial cells; high glucose; diabetic nephropathy STORE-OPERATED Ca 2ϩ entry (SOCE) via store-operated Ca 2ϩ channels (SOCs) is a ubiquitous signaling mechanism in both nonexcitable and excitable cells. This Ca 2ϩ signaling regulates diverse cellular functions ranging from cell proliferation and gene expression to cell contraction and secretion (35). Although SOCE was originally described over two decades ago, its molecular mediators were unknown until recently. By high-throughput RNA inhibition screening, two protein families, stromal interacting molecule (STIM) (27, 36) and Orai (13, 48, 59), were identified as required components of SOCE. STIM1 is a single-pass transmembrane protein located primarily in the endoplasmic reticulum (ER) membrane and functions as an ER Ca 2ϩ sensor to sense the ER luminal Ca 2ϩ concentration. Orai1 is a small plasma membrane protein and is believed to be the pore-forming unit of SOCs. Upon depletion of ER Ca 2ϩ , STIM1 aggregates and translocates to ER-plasma membrane junctions, where it physically associates and subsequently activates Orai1 and causes Ca 2ϩ entry into the cytosol (...

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Section: Discussionsupporting

confidence: 58%

Section: Discussionsupporting

confidence: 56%

Impairment of hepatic nuclear factor-4α binding to theStim1promoter contributes to high glucose-induced upregulation of STIM1 expression in glomerular mesangial cells

Wang

Chaudhari

Ren

et al. 2015

American Journal of Physiology-Renal Physiology

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“…The Ca 2þ concentration was measured using the Ca 2þ -sensitive fluorescent dye Fura-2/AM, as described previously (58). Briefly, cells were grown to confluence on fibronectin-coated coverslips, then washed with Hanks balanced salt solution (HBSS), loaded with 3 mM Fura-2 for 30 min in HBSS, then washed again three to four times with Ca-free HBSS and mounted on a slide holder to a semimotorized microscope (Axio Observer D1, Carl Zeiss, Jena, Germany) equipped with an AxioCam HSm camera (Carl Zeiss) and a Fluar 40Â oil immersion objective.…”

Section: Measurements Of Cytosolic Ca 2þmentioning

confidence: 99%

Molecular-Scale Biophysical Modulation of an Endothelial Membrane by Oxidized Phospholipids

Ayee

LeMaster

Shentu

et al. 2017

Biophysical Journal

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The influence of two bioactive oxidized phospholipids on model bilayer properties, membrane packing, and endothelial cell biomechanics was investigated computationally and experimentally. The truncated tail phospholipids, 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) and 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC), are two major oxidation products of the unsaturated phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-phosphocholine. A combination of coarse-grained molecular dynamics simulations, Laurdan multiphoton imaging, and atomic force microscopy microindentation experiments was used to determine the impact of POVPC and PGPC on the structure of a multicomponent phospholipid bilayer and to assess the consequences of their incorporation on membrane packing and endothelial cell stiffness. Molecular simulations predicted differential bilayer perturbation effects of the two oxidized phospholipids based on the chemical identities of their truncated tails, including decreased bilayer packing, decreased bilayer bending modulus, and increased water penetration. Disruption of lipid order was consistent with Laurdan imaging results indicating that POVPC and PGPC decrease the lipid packing of both ordered and disordered membrane domains. Computational predictions of a larger membrane perturbation effect by PGPC correspond to greater stiffness of PGPC-treated endothelial cells observed by measuring cellular elastic moduli using atomic force microscopy. Our results suggest that disruptions in membrane structure by oxidized phospholipids play a role in the regulation of overall endothelial cell stiffness.

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“…However, we hypothesize that a direct activation of neuronal TLR4 would require local tissue infection or endotoxin extravasation. The latter might occur if the well-described endotoxin-induced vascular hyperpermeability is taken into consideration (9). Nevertheless, intact bacterial lipopolysaccharides are Յ20-kDa macromolecules, and vascular leakage is size-selective (7).…”

Section: G859mentioning

confidence: 99%

Myocyte TLR4 enhances enteric and systemic inflammation driving late murine endotoxic ileus

Buchholz

Shapiro

Vodovotz

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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Cooperative Signaling via Transcription Factors NF-κB and AP1/c-Fos Mediates Endothelial Cell STIM1 Expression and Hyperpermeability in Response to Endotoxin

Cited by 54 publications

References 53 publications

Impairment of hepatic nuclear factor-4α binding to theStim1promoter contributes to high glucose-induced upregulation of STIM1 expression in glomerular mesangial cells

Impairment of hepatic nuclear factor-4α binding to theStim1promoter contributes to high glucose-induced upregulation of STIM1 expression in glomerular mesangial cells

Molecular-Scale Biophysical Modulation of an Endothelial Membrane by Oxidized Phospholipids

Myocyte TLR4 enhances enteric and systemic inflammation driving late murine endotoxic ileus

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