Autoimmune activation and hypersensitization of the AT1 and ETA receptors contributes to vascular injury in scleroderma renal crisis.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Selenium and Copper as Biomarkers for Pulmonary Arterial Hypertension in Systemic Sclerosis.

Circulating selenoprotein P (SELENOP) constitutes an established biomarker of Se status. SELENOP concentrations are reduced in inflammation and severe disease. Recently, elevated SELENOP levels have been suggested as diagnostic marker and therapeutic target in pulmonary arterial hypertension (PAH). We decided to re-evaluate this hypothesis. A group of healthy controls (n = 30) was compared with patients suffering from systemic sclerosis (SSc, n = 66), one third with SSc-related PAH. Serum was analysed for trace elements and protein biomarkers, namely SELENOP, glutathione peroxidase 3 (GPx3) and ceruloplasmin (CP). Compared to controls, patients with SSc-related PAH displayed reduced serum Se (91 ± 2 vs. 68 ± 2 µg/L) and SELENOP concentrations (3.7 ± 0.8 vs. 2.7 ± 0.9 mg/L), along with lower GPx3 activity (278 ± 40 vs. 231 ± 54 U/L). All three biomarkers of Se status were particularly low in patients with skin involvement. Serum Cu was not different between the groups, but patients with SSc-related PAH showed elevated ratios of Cu/Se and CP/SELENOP as compared to controls. Our data indicate that patients with SSc-related PAH are characterized by reduced Se status in combination with elevated CP, in line with other inflammatory diseases. Further analyses are needed to verify the diagnostic value of these TE-related biomarkers in PAH.