L-sepiapterin restores SLE serum-induced markers of endothelial function in endothelial cells

Buie, Joy N. Jones; Jenkins, Dorea P.; Muise‐Helmericks, Robin C.; Oates, Jim C.

doi:10.1136/lupus-2018-000294

Cited by 8 publications

(6 citation statements)

References 56 publications

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“…[20][21][22][23][24][25][26] Our laboratory has published that eNOS is uncoupled with addition of lupus serum. 17 This uncoupling leads to production of reactive oxygen species in an animal model of LN and in LN glomerular tissue. 12 27 Therefore, reduction oxidation (redox) signalling may be a common intracellular mechanism in endothelial cell activation.…”

Section: Discussionmentioning

confidence: 99%

“…The fluorescence intensity of migrated neutrophils in the lower chamber was measured as described. 17 All values were normalised to untreated controls.…”

Section: Methodsmentioning

confidence: 99%

“…The linear equation was then calculated and fluorescence intensity of samples could then be input into the linear equation to determine neutrophil cell number. The fluorescence intensity of migrated neutrophils in the lower chamber was measured as described 17. All values were normalised to untreated controls.…”

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confidence: 99%

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Lupus serum induces inflammatory interaction with neutrophils in human glomerular endothelial cells

2020

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ObjectivesSLE is associated with endothelial cell dysfunction (ECD). Understanding how ECD leads to neutrophil infiltration into glomeruli is essential to finding therapeutic targets for SLE. The aim of this study is to determine the effect of SLE serum from patients with active disease to induce neutrophil adhesion to and chemotaxis towards glomerular endothelial cells and factors induced by serum that associate with neutrophil chemotaxis.MethodsPatients with SLE had serum collected during paired longitudinal visits with lower and higher activity. 13 patients with SLE (5 SLE, 5 SLE with hypertension (HTN) and 3 SLE lupus nephritis (LN) and HTN), and 10 healthy controls (5 with and 5 without HTN) were examined. The adhesion of neutrophils to serum-treated human renal glomerular endothelial cells (HRGECs) or chemotaxis of neutrophils towards conditioned media from serum-treated HRGECs was determined, and levels of cytokines in this conditioned medium were quantified. Pathway analysis of cytokines induced by SLE and LN serum that associated with neutrophil migration was performed.ResultsHRGECs treated with SLE serum induced significantly greater neutrophil chemotaxis and adhesion compared with control serum. When examining specific cohorts, SLE HTN and LN HTN promoted greater neutrophil chemotaxis than control serum, while SLE HTN and LN HTN promoted greater chemotaxis than SLE serum. Serum from active disease visits promoted neutrophil chemotaxis and adhesion over paired inactive visits. Levels of platelet-derived growth factor-BB, interleukin (IL)-15 and IL-8 secreted by SLE serum-treated HRGECs positively correlated with neutrophil chemotaxis. Pathway analysis suggested that LN serum induced pathways important in endoplasmic reticulum and oxidative stress.ConclusionsSLE serum induces expression of mediators by HRGECs that promote neutrophil chemotaxis and adhesion, which increases during disease activity, and associates with factors common to pathways of endoplasmic reticulum and oxidative stress. These findings highlight the potential importance of serum factor-induced ECD in SLE and LN.

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Section: Discussionmentioning

confidence: 99%

“…The fluorescence intensity of migrated neutrophils in the lower chamber was measured as described. 17 All values were normalised to untreated controls.…”

Section: Methodsmentioning

confidence: 99%

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Lupus serum induces inflammatory interaction with neutrophils in human glomerular endothelial cells

2020

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“…In a murine model of SLE, eNOS was found to be inhibited through phosphorylation, while superoxide production is increased in aortic endothelium, with an impaired vasodilatory reaction to acetylcholine, a transversal benchmark for endothelium‐dependent vasorelaxation 29 . In another study performed on human umbilical vein endothelial cells from SLE patients and matched controls, altered NOS activity and NO‐modulated cascades were proved to be linked to compromised ECs 30 . These findings are further supported by genetic studies on eNOS polymorphisms as risk factors for SLE 31,32 …”

Section: Endothelial Dysfunction In Sle and Lnmentioning

confidence: 99%

Endothelial dysfunction and cardiovascular risk in lupus nephritis: New roles for old players?

Mancardi

Arrigo

Cozzi

et al. 2020

Eur J Clin Investigation

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In systemic lupus erythematosus (SLE) patients, most of the clinical manifestation share a vascular component triggered by endothelial dysfunction. Endothelial cells (ECs) activation occurs both on the arterial and venous side, and the high vascular density of kidneys accounts for the detrimental outcomes of SLE through lupus nephritis (LN). Kidney damage, in turn, exerts a negative feedback on the cardiovascular (CV) system aggravating risk factors for CV diseases such as hypertension, stroke and coronary syndrome among others. Despite the intensive investigation on SLE and LN, the role of endothelial dysfunction, as well as the underlying mechanisms, remains to be fully understood, with no specifically targeted pharmacological treatment. It is not known, in fact, if the activation pathway(s) in venous ECs are similar to the one in arterial ECs and doubts persist on the shared manifestation of microcirculation compared to macrocirculation. In this work, we aim to review the recent literature about the role of endothelial activation and dysfunction in the development of CV complications in SLE and LN patients. We, therefore, focus on arteriovenous similarities and differences and on specific pathways of great vessels compared to capillaries. Critically summarising the available data is of pivotal importance for both basic researchers and clinicians in order to develop and test new pharmacological approaches in the treatment of basic components of SLE and LN.

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“…Endothelial injury leads to impaired vascular tone and permeability and reduced NO release resulting in diminished endothelium-dependent vasodilation and subsequent atherosclerotic lesion in SLE patients. Endothelial NOS (eNOS) expression inversely correlates with the degree of glomerular injury in LN patients, mediated in part through increased IFN-α signature ( 60 , 61 ). Atherogenic risk and intimal-medial thickening have been reported to inversely correlate with the thickness of the glycocalyx ( 62 ).…”

Section: Endothelial Injury In Lupus Nephritismentioning

confidence: 99%

Endothelial cell activation and glycocalyx shedding - potential as biomarkers in patients with lupus nephritis

Yung,

Chan

2023

Front. Immunol.

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Lupus nephritis (LN) is a common and severe manifestation of systemic lupus erythematosus and an important cause of acute and chronic kidney injury. Early diagnosis of LN and preventing relapses are key to preserving renal reserve. However, due to the complexity and heterogeneity of the disease, clinical management remains challenging. Kidney biopsy remains the gold standard for confirming the diagnosis of LN and subsequent assessment of kidney histopathology, but it is invasive and cannot be repeated frequently. Current clinical indicators of kidney function such as proteinuria and serum creatinine level are non-specific and do not accurately reflect histopathological changes, while anti-dsDNA antibody and C3 levels reflect immunological status but not kidney injury. Identification of novel and specific biomarkers for LN is prerequisite to improve management. Renal function deterioration is associated with changes in the endothelial glycocalyx, a delicate gel-like layer located at the interface between the endothelium and bloodstream. Inflammation induces endothelial cell activation and shedding of glycocalyx constituents into the circulation. This review discusses the potential role of soluble glycocalyx components as biomarkers of active LN, especially in patients in whom conventional serological and biochemical markers do not appear helpful.

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L-sepiapterin restores SLE serum-induced markers of endothelial function in endothelial cells

Cited by 8 publications

References 56 publications

Lupus serum induces inflammatory interaction with neutrophils in human glomerular endothelial cells

Lupus serum induces inflammatory interaction with neutrophils in human glomerular endothelial cells

Endothelial dysfunction and cardiovascular risk in lupus nephritis: New roles for old players?

Endothelial cell activation and glycocalyx shedding - potential as biomarkers in patients with lupus nephritis

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