Autoimmune activation and hypersensitization of the AT1and ETAreceptors contributes to vascular injury in scleroderma renal crisis

Björn Hegner, Tobias Kretzschmar, Nan Zhu, Gunnar Kleinau, Hongfan Zhao, Julian Kamhieh-Milz, Julia Hilger, Ralf Schindler, Patrick Scheerer, Gabriela Riemekasten, Aurlie Philippe, Rusan Catar*

*Corresponding author for this work
4 Citations (Scopus)

Abstract

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.

Original languageEnglish
JournalRheumatology (United Kingdom)
Volume62
Issue number6
Pages (from-to)2284-2293
Number of pages10
ISSN1462-0324
DOIs
Publication statusPublished - 01.06.2023

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)

DFG Research Classification Scheme

  • 205-18 Rheumatology
  • 204-05 Immunology

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