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 (AT(1)R) 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 AT(1)R 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 AT(1)R and ETAR. This relied on MEK-ERK signalling indicating functional relevance of anti-AT(1)R and anti-ETAR Abs. The contractile response to angiotensin II and endothelin-1 was amplified by patient IgG containing anti-AT(1)R 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 AT(1)R and ETAR might improve outcomes in severe cases of SRC.

Automated summary

This study provides experimental evidence that activating autoantibodies may contribute to scleroderma renal crisis (SRC). This effect is likely related to direct receptor stimulation and additional allosteric effects. Novel therapies targeting autoimmune hyperactivation of the angiotensin II type 1 receptor (AT(1)R) and the endothelin-1 type A receptor (ETAR) may improve outcomes in severe cases of SRC.