HLA-B35 Upregulates Endothelin-1 and Downregulates Endothelial Nitric Oxide Synthase via Endoplasmic Reticulum Stress Response in Endothelial Cells

Lenna, Stefania; Townsend, Danyelle M.; Tan, Filemon K.; Kapanadze, Bagrat; Markiewicz, M; Trojanowska, Maria; Scorza, Raffaella

doi:10.4049/jimmunol.0903188

Cited by 43 publications

(42 citation statements)

References 58 publications

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“…It is well documented that inhibition of ER stress by 4-phenylbutyric acid, an ER stress inhibitor, is able to protect cardiac and renal fibrosis in animal models [7,8,9]. With respect to inflammatory responses, it has been reported that ER stress is able to elicit inflammatory responses through activation of NF-κB and the MAPK JNK [10], induction of cytokines such as IFN-β, IL-23, endothelin-1 [11,12,13], activation of the NLRP3 inflammasome [14] and release of TGF-β and expression of collagen I [15]. Thus, prevention and/or reversal of ER stress may serve as one of the possible therapeutic approaches to organ fibrosis and inflammation.…”

Section: Introductionmentioning

confidence: 99%

Up-Regulation of SIRT1 Reduces Endoplasmic Reticulum Stress and Renal Fibrosis

Chang

Kim

Baek

et al. 2016

Nephron

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Background: Endoplasmic reticulum (ER) stress is emerging as an important factor in the development of organ fibrosis. Therefore, modulation of ER stress may serve as one of the possible therapeutic approaches to renal fibrosis. SIRT1, a class III histone deacetylase, has been found to exert beneficial effects in kidney diseases. However, it is largely unknown whether and how SIRT1 suppresses the ER stress. We postulated that upregulation of SIRT1 would suppress the ER stress through induction of heme oxygenase-1 (HO-1) and thioredoxin. Methods: HK-2 tubular cells, experimental mouse models of tunicamycin (TM)-induced ER stress and unilateral ureteral obstruction (UUO) were used. Expression of ER stress-induced protein was measured by Western blot analysis and immunohistochemical staining. ER stress was induced by chemical ER stress inducers [TM [,]thapsigargin (TG)] and non-chemical inducers such as angiotensin II, aldosterone, high glucose and albumin. Results: SIRT1 activator (SRT1720) induced SIRT1 expression in a time- and dose-dependent manner in HK-2 cells. SRT1720 suppressed the TM- or TG-induced ER stress, as shown by inhibition of TM- or TG-induced upregulation of glucose-related protein 78 (GRP78), phosphor-specific eukaryotic translation initiation factor-2α and C/EBP homologous protein through HO-1 and thioredoxin, which were abolished by pretreatment with SIRT1 inhibitor (sirtinol). SRT1720 also suppressed the ER stress induced by angiotensin II, aldosterone, high glucose and albumin. In animal studies, treatment with SRT1720 reduced the tubular expression of GRP78 and increased the expression of HO-1 and thioredoxin. SRT1720 also reduced the UUO-induced renal fibrosis. Conclusion: SIRT1 may serve as a promising therapeutic target by reducing ER stress and fibrosis.

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Section: Introductionmentioning

confidence: 99%

Up-Regulation of SIRT1 Reduces Endoplasmic Reticulum Stress and Renal Fibrosis

Chang

Kim

Baek

et al. 2016

Nephron

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“…23-26 The negative effect of ER stress induction on eNOS expression has been recently described in endothelial cells in a model of isolated pulmonary hypertension, and in muscle from CHOP−/− mice. 27,28 Because endothelial nitric oxide synthase (eNOS) plays an important role in maintaining blood pressure and vascular function, our aim is to determine the cellular mechanisms that link ER stress to oxidative stress and how it affects eNOS expression and activity in vascular endothelial cell.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of endoplasmic reticulum stress-induced vascular endothelial dysfunction

Galán

Kassan

Kadowitz

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

121

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Background We recently reported that ER stress plays a key role in vascular endothelial dysfunction during hypertension. In this study we aimed to elucidate the mechanisms by which ER stress induction and oxidative stress impair vascular endothelial function. Methodology/Principal findings we conducted in vitro studies with primary endothelial cells from coronary arteries stimulated with tunicamycin, 1 μg/mL, in the presence or absence of two ER stress inhibitors: tauroursodeoxycholic acid (Tudca), 500 μg/mL, and 4-phenyl butyric acid (PBA), 5 mM. ER stress induction was assessed by enhanced phosphorylation of PERK and eIF2α, and increased expression of CHOP, ATF6 and Grp78/Bip. The ER stress induction increased p38 MAPK phosphorylation, Nox2/4 mRNA levels and NADPH oxidase activity, decreased eNOS promoter activity, eNOS expression and phosphorylation, and nitrite levels. Interestingly, the inhibition of p38 MAPK pathway reduced CHOP and Bip expression enhanced by tunicamycin and restored eNOS promoter activation as well as phosphorylation. To study the effects of ER stress induction in vivo, we used C57BL/6J mice and p47phox−/− mice injected with tunicamycin or saline. The ER stress induction in mice significantly impaired vascular endothelium-dependent and independent relaxation in C57BL/6J mice compared with p47phox−/− mice indicating NADPH oxidase activity as an intermediate for ER stress in vascular endothelial dysfunction. Conclusion/Significance We conclude that chemically induced ER stress leads to a downstream enhancement of p38 MAPK and oxidative stress causing vascular endothelial dysfunction. Our results indicate that inhibition of ER stress could be a novel therapeutic strategy to attenuate vascular dysfunction during cardiovascular diseases.

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“…It has been controversial whether eNOS is one of inducing factors for ER stress in endothelial cells. In the systemic cardiovascular system, ER stress results in endothelial dysfunction characterized by reduced eNOS activity and NO bioavailability (Reiter et al, 2000;Lenna et al, 2010;Loinard et al, 2012;Galán et al, 2014). Unlike the systemic circulatory system, NOS expression/activity plays an important role in BBB disruption in the brain vascular system (Mohammadi et al, 2012;Ding et al, 2014;Jiang et al, 2014) Indeed, NO is critical for dysfunction of vascular endothelial cells via ER stress, which facilitates endothelial dysfunction in the brain capillary (Kito et al, 2011;Zhang et al, 2014).…”

Section: Discussionmentioning

confidence: 99%