endothelin-1 and Scleroderma--Localized

Scleroderma renal crisis (SRC) is a rare vascular complication of systemic sclerosis with substantial risks for end-stage renal disease and premature death. Activating autoantibodies (Abs) targeting the angiotensin II type 1 (AT1R) and the endothelin-1 type A receptor (ETAR) have been identified as predictors for SRC. Here, we sought to determine their pathogenic significance for acute renal vascular injury potentially triggering kidney failure and malignant hypertension.. IgG from patients with SRC was studied for AT1R and ETAR dependent biologic effects on isolated rat renal interlobar arteries and vascular cells including contraction, signalling and mechanisms of receptor activation.. In myography experiments, patient IgG exerted vasoconstriction sensitive to inhibition of AT1R and ETAR. This relied on MEK-ERK signalling indicating functional relevance of anti-AT1R and anti-ETAR Abs. The contractile response to angiotensin II and endothelin-1 was amplified by patient IgG containing anti-AT1R and anti-ETAR Abs with substantial crosstalk between both receptors implicating autoimmune receptor hypersensitization. Co-immunoprecipitation experiments indicated heterodimerization between both receptor types which may enable the observed functional interrelation by direct structural interactions.. We provide experimental evidence that agonistic Abs may contribute to SRC. This effect is presumably related to direct receptor stimulation and additional allosteric effects, at least in heterodimeric receptor constellations. Novel therapies targeted at autoimmune hyperactivation of AT1R and ETAR might improve outcomes in severe cases of SRC.

Topics: Acute Kidney Injury; Angiotensin II; Animals; Autoantibodies; Endothelin-1; Immunoglobulin G; Rats; Receptor, Endothelin A; Scleroderma, Localized; Vascular System Injuries

There are several pathogenetic models of localized scleroderma. At the same time, studies examining the role of endothelin-1, vascular endothelial growth factor (VEGF-A) and cell adhesion molecule-1 (VCAM) are limited. Objectives - to learn the nature of disorders of vascular, proliferative, adhesive functions of the endothelium on the content of endothelin-1, VEGF-A and VCAM-1 in localized scleroderma. The study included 78 patients with localized scleroderma and 35 healthy individuals (mean age - 44.2±17.6 years, 73 women (64.6%), 40 men (35.4%). All patients underwent clinical, laboratory, enzyme-linked immunosorbent assay examination (endothelin-1, VEGF-A, VCAM-1). In the local form of scleroderma, there are the number of disorders of vascular, proliferative and adhesive functions of the endothelium, with an increase in endothelin-1 (p<0.05), VEGF-A (p<0.05) and VCAM-1 (p<0.05) content. In idiopathic atrophodermia, the level of endothelin-1 was probably higher (p<0.05). The vasospastic type of pathogenesis of localized scleroderma was established in patients under 20 years of age (p<0.05) and in patients older than 70 years (p<0.05). U-shaped age dependence of pathogenesis was noted: high content of VEGF-A in patients under 20 years of age (p<0.05) and after 35 years (p<0.05). Higher levels of VCAM-1 were found in women compared to men (p<0.05). The analysis of the age dependence of the content revealed a U-shaped dependence of VCAM-1 - the highest content in patients under 20 years (p<0.05) and in patients 55-70 years (p<0.05). The level of biomarkers of endothelial dysfunction in patients with localized scleroderma - endothelin-1, VEGF and VCAM is associated with different phenotypes of the disease course - vasospastic, proliferative or adhesive.

Topics: Adult; Aged; Endothelin-1; Endothelium, Vascular; Female; Humans; Male; Middle Aged; Phenotype; Scleroderma, Localized; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factor A; Young Adult

To evaluate the influence of endothelin-1 (ET-1) and sex hormones on cell proliferation and extracellular matrix (ECM) synthesis (ie, fibronectin, laminin) by cultured normal and scleroderma (SSc) human skin fibroblasts (FBs).. Primary cultures of FBs were treated with ET-1 and sex hormones (17beta-oestradiol or testosterone) for 24 h. Cell growth was analysed by methiltetrazolium salt test, ECM synthesis was evaluated by immunocytochemistry and western blot, both at 24 h.. In normal FBs, ET-1 and 17beta-oestradiol, as well as their combination, increased cell growth (p<0.001, p<0.001, p<0.01 vs untreated cells (control), respectively) and fibronectin synthesis (p<0.05, p<0.05, p<0.01 vs control, respectively). By contrast, testosterone either alone or in combination with ET-1 did not influence cell proliferation, but decreased fibronectin synthesis (p<0.05, testosterone vs control). In SSc FBs, ET-1 and 17beta-oestradiol alone or their combination induced an increased fibronectin synthesis (p<0.05, p<0.05, p<0.01 vs control, respectively). Unexpectedly, testosterone induced an increase of fibronectin synthesis (p<0.05 vs control).. ET-1 and 17beta-oestradiol seem to exert a profibrotic effect in normal and SSc culture FBs and might suggest their synergistic effect in the pathogenesis of the fibrotic process in SSc.

Topics: Blotting, Western; Case-Control Studies; Cell Proliferation; Cells, Cultured; Drug Synergism; Endothelin-1; Estradiol; Extracellular Matrix; Female; Fibroblasts; Fibronectins; Gonadal Steroid Hormones; Humans; Immunohistochemistry; Male; Scleroderma, Localized; Skin; Statistics, Nonparametric; Testosterone

According to current knowledge, endothelin (ET)-1 plays an important role in the pathogenesis of systemic sclerosis (SSc). We assessed ET plasma levels in SSc patients according to the clinical presentation and the presence of complications such as pulmonary arterial hypertension (PAH).. Sixty-three consecutive patients with SSc were included. The control group included 17 healthy patients. ET plasma level was determined for all patients. Pulmonary function test and pulmonary high resolution computed tomography were performed in 44 patients and echocardiography in 51 patients, to screen for PAH, always confirmed by a right heart catheterization.. ET plasmatic levels were higher in SSc patients than in healthy group subjects but the difference was not significant (3.72+/-1.13 vs 3.40+/-0.71 pmol/l, p=0.27). ET plasmatic levels were significantly higher in patients with PAH than in patients without PAH (4.28+/-0.65 vs 3.62+/-1.07 pmol/l, p=0.04) and in patients with anticentromere antibodies (3.96+/-1.11 vs 3.19+/-1.12 pmol/l, p=0.03). There was a positive linear correlation between ET plasmatic levels and systolic pulmonary arterial pressure (r=0.34, p=0.013). The best cut-off value for ET plasmatic level to discriminate patients affected by PAH was determined by ROC curve method: 4.1 pmol/l (sensibility 85.7%, specificity 66%).. ET plasmatic levels were higher in SSc patients affected by PAH and patients with anticentromere antibodies. There was a positive linear correlation between ET plasmatic levels and systolic pulmonary arterial pressure. Assessment of ET plasmatic levels for detection and monitoring of pulmonary hypertension during SSc is warranted in larger prospective studies.

Topics: Aged; Biomarkers; Cardiac Catheterization; Echocardiography; Endothelin-1; Female; Humans; Male; Middle Aged; Radiography; Reference Values; ROC Curve; Scleroderma, Localized; Scleroderma, Systemic