High glucose enhances store-operated calcium entry by upregulating ORAI/STIM via calcineurin-NFAT signalling

Daskoulidou, Nikoleta; Zeng, Bo; Berglund, Lisa M.; Jiang, Huai; Chen, Gui Lan; Kotova, Olga; Bhandari, Sunil; Ayoola, James; Griffin, Steven; Atkin, Stephen L.; Gomez, Maria F.; Xu, Shang‐Zhong

doi:10.1007/s00109-014-1234-2

Cited by 42 publications

(49 citation statements)

References 41 publications

(40 reference statements)

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“…Like in platelets and vascular endothelial cells (4,58), prolonged HG treatment in MCs increased STIM1/Orai1 protein expression levels and augmented SOCE. In a recent study (53), we further showed that activation of STIM1/Orai1-mediated SOCs reduced fibronectin and collagen type IV expression, suggesting a renoprotective effect of SOCE.…”

Section: Discussionmentioning

confidence: 97%

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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: Discussionmentioning

confidence: 97%

“…Diabetes/HG effects on STIM1 expression/SOC function are cell context dependent (1,3,4,30,34,58). Like in platelets and vascular endothelial cells (4,58), prolonged HG treatment in MCs increased STIM1/Orai1 protein expression levels and augmented SOCE.…”

Section: Discussionmentioning

confidence: 99%

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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“…A recent study by Daskoulidou et al (15) described the upregulation of all STIM and Orai proteins by chronic treatment with high glucose (25 mM), which correlated with enhanced SOCE in response to store depletion in vascular endothelial cells. This upregulation could be prevented by cyclosporin A and knockdown of NFATc3, leading the authors to conclude that upregulation of STIM/Orai proteins by hyperglycemia is mediated by the calcineurin/NFAT pathway, which enhances SOCE and causes endothelial dysfunction (15).…”

Section: Soce In Smooth Musclementioning

confidence: 94%

“…This upregulation could be prevented by cyclosporin A and knockdown of NFATc3, leading the authors to conclude that upregulation of STIM/Orai proteins by hyperglycemia is mediated by the calcineurin/NFAT pathway, which enhances SOCE and causes endothelial dysfunction (15). The enhanced expression of STIM/Orai isoforms was also observed in aortas from diabetic patients and from two different animal models of diabetes (15 (65) to propose an additional role for Orai3 in regulating basal levels of ER Ca 2ϩ or in mediating Ca 2ϩ release from internal stores. The allergen-induced mucosal injury characteristic of asthmatic airways is believed to initiate a repair cascade that involves secretion of growth factors, including PDGF, which stimulate airway SMCs (95).…”

Section: Soce In Smooth Musclementioning

confidence: 99%

Orai channel-mediated Ca²⁺signals in vascular and airway smooth muscle

Spinelli

Trebak

2016

American Journal of Physiology-Cell Physiology

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“…44,[51][52][53][54][55][56][57][58][59][60] Over the past decade, accumulating evidence has demonstrated that many diabetic complications involve alterations of SOCE and its signaling pathways. [60][61][62][63][64] Since diabetes and its complications are becoming epidemic worldwide and there is no curative therapy currently available for diabetic complications, [65][66][67] continued exploration of the basic pathophysiology of diabetic complications and of new therapeutic approaches is in need. This review summarizes the published studies on the associations of abnormal SOCE with the pathology of diabetic complications.…”

Section: Introductionmentioning

confidence: 99%

Store-operated calcium entry and diabetic complications

Chaudhari

2015

Exp Biol Med (Maywood)

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Store-operated Ca 2þ entry (SOCE) is mediated by the store-operated Ca 2þ channel (SOC) that opens upon depletion of internal Ca 2þ stores following activation of G protein-coupled receptors or receptor tyrosine kinases. Over the past two decades, the physiological and pathological relevance of SOCE has been extensively studied. Recently, accumulating evidence suggests associations of altered SOCE with diabetic complications. This review focuses on the implication of SOCE as it pertains to various complications resulting from diabetes. We summarize recent findings by us and others on the involvement of abnormal SOCE in the development of diabetic complications, such as diabetic nephropathy and diabetic vasculopathy. The underlying mechanisms that mediate the diabetes-associated alterations of SOCE are also discussed. The SOCE pathway may be considered as a potential therapeutic target for diabetes-associated diseases.

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High glucose enhances store-operated calcium entry by upregulating ORAI/STIM via calcineurin-NFAT signalling

Cited by 42 publications

References 41 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

Orai channel-mediated Ca²⁺signals in vascular and airway smooth muscle

Store-operated calcium entry and diabetic complications

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High glucose enhances store-operated calcium entry by upregulating ORAI/STIM via calcineurin-NFAT signalling

Cited by 42 publications

References 41 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

Orai channel-mediated Ca2+signals in vascular and airway smooth muscle

Store-operated calcium entry and diabetic complications

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Orai channel-mediated Ca²⁺signals in vascular and airway smooth muscle