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

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

doi:10.1093/rheumatology/keac594

Cited by 8 publications

(7 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hegner et al . [20 ▪ ] showed that the vasocontractile response of endothelial cells to angiotensin II and endothelin-1 (ET-1) was amplified by IgG from SSc patients with SRC through substantial crosstalk between AT1R and ETAR. AT1R and ETAR belong to a family of G-protein coupled receptors (GPCRs), which are now recognized as preferential autoantibody targets in patients with SSc and other autoimmune diseases [21].…”

Section: Vascular Injurymentioning

confidence: 99%

Pathogenesis of vasculopathy in systemic sclerosis and its contribution to fibrosis

Kawaguchi

Kuwana

2023

Current Opinion in Rheumatology

View full text Add to dashboard Cite

Purpose of review In patients with systemic sclerosis (SSc), vascular manifestations precede skin and organ fibrosis. There is increasing evidence demonstrating a pathogenic link between early vascular injury and subsequent development of tissue fibrosis. Recent findings Our knowledge of cellular and molecular mechanisms underlying a unique relationship between SSc-related vasculopathy and fibrosis has changed over the last few years. There is increasing evidence showing viral infection as a potential trigger elucidating vascular injury. Due to defective vascular repair machinery, this initial event results in endothelial cell activation and apoptosis as well as the recruitment of inflammatory/immune cells, leading to endothelial-to-mesenchymal transition. This sequential process induces destructive vasculopathy in capillaries, fibroproliferative vascular lesions in arteries, and excessive fibrosis in the surrounding tissue. A variety of molecular mechanisms and pathways involved in vascular remodeling linked to subsequent excessive fibrosis have been identified and serve as attractive therapeutic targets for SSc. Summary Endothelial injury may play a central role in connecting three features that characterize SSc pathogenesis: vasculopathy, chronic inflammation, and fibrosis. Our understanding of the processes responsible for myofibroblast differentiation triggered by vascular injury will provide the rationale for novel targeted therapies for SSc.

show abstract

Section: Vascular Injurymentioning

confidence: 99%

Pathogenesis of vasculopathy in systemic sclerosis and its contribution to fibrosis

Kawaguchi

Kuwana

2023

Current Opinion in Rheumatology

View full text Add to dashboard Cite

show abstract

“…7 Mechanistically, anti-AT 1 R and anti-ET A R Abs not only activate endothelial cells 8 but also elicit contraction in renal resistance arteries. 9 Importantly, we found evidence that Abs targeting the AT 1 R and the ET A R hypersensitize the receptors to their natural ligands angiotensin II (Ang II) and ET-1. 9 This might facilitate the excessive vasoconstriction found in SRC and enhance the vicious cycle of vascular injury, reduced renal blood supply, and RAAS activation.…”

Section: Introductionmentioning

confidence: 89%

Intensive receptor blockade and plasma exchange to treat refractory scleroderma renal crisis in patients with agonistic autoantibodies targeting the angiotensin II type 1 and endothelin-1 type A receptors

Hegner

Callaghan

Schindler

et al. 2023

Journal of Scleroderma and Related Disorders

Self Cite

View full text Add to dashboard Cite

Scleroderma renal crisis is a rare complication of systemic sclerosis characterized by a rapid decline in kidney function due to acute renal vascular injury. Recently, activating autoantibodies targeting the angiotensin II type 1 receptor and the endothelin-1 type A receptor have been implicated in the pathophysiology of scleroderma renal crisis by sensitizing the angiotensin II type 1 receptor and endothelin-1 type A receptor in renal resistance arteries to their natural ligands. Here, we describe a cohort of 10 patients with scleroderma renal crisis refractory to standard treatment, including blockade of the renin-angiotensin system. Multimodal therapy was initiated, targeting at the removal of anti-angiotensin II type 1 receptor and anti-endothelin-1 type A receptor autoantibodies by plasma exchange and the reduction of vasoconstrictive activity. Further treatment options included angiotensin II type 1 receptor and endothelin-1 type A receptor blockade, iloprost, intravenous immunoglobulins, and immunosuppression. Six patients were hypertensive. On kidney biopsy, concentric intimal sclerosis was present in all patients, whereas acute vascular injury was evident in eight. Levels of anti-angiotensin II type 1 receptor and anti-endothelin-1 type A receptor autoantibodies were significantly reduced by multimodal treatment. Kidney function improved in three patients with histological signs of severe acute renal vascular damage. This report demonstrates that intensive multimodal therapy taking account of potentially pathogenic anti-angiotensin II type 1 receptor and anti-endothelin-1 type A receptor autoantibodies in concert with other vasodilatory interventions provides a salvage option for patients with refractory scleroderma renal crisis.

show abstract

“…Protein-DNA complexes were analyzed by electrophoresis in 6% non-denaturing polyacrylamide gels and visualized with LightShift Chemiluminescent EMSA Kit (Thermo). The activity of NFkB and NFAT signaling was analyzed with EMSA and luciferase assays, respectively, as described previously ( 50 , 51 ).…”

Section: Methodsmentioning

confidence: 99%

“…(A, B) Effect of KTx-IgG on TNF-α protein release from HMECs (A) Upon a 24-hour incubation with 1.0 mg/ml Con-IgG or KTx-IgG from patients with or without vasculopathy or baseline control (pg/ml, n=3 each) and (B) Upon a 24-hour stimulation with 1 mg/ml KTx-IgG from patients with vasculopathy (n=5 each) in the presence or absence of the following stimuli: a) mitogen phorbol-myristate-acetate (PMA, concentration 50 ng/ml), b) thrombin (0.1 U/ml), and c) PAR-1 inhibitor (BMS200261, 1 µM); and (C, D) Analysis of NFkB and NFAT activation in response to KTx-IgG from patients with vasculopathy compared to Con-IgG (each 1 mg/ml for 24 hours). The activity of NFkB and NFAT signaling was analyzed with EMSA and luciferase assays, respectively, as described previously ( 50 , 51 ). The data were analyzed with repeated ANOVA and expressed as Mean +/- SD with *P<0.05, **P<0.01, and ***P<0.001.…”

Section: Supplementary Materialsmentioning

confidence: 99%

Autoantibodies from patients with kidney allograft vasculopathy stimulate a proinflammatory switch in endothelial cells and monocytes mediated via GPCR-directed PAR1-TNF-α signaling

Moll,

Luecht,

Gyamfi

et al. 2023

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

Non-HLA-directed regulatory autoantibodies (RABs) are known to target G-protein coupled receptors (GPCRs) and thereby contribute to kidney transplant vasculopathy and failure. However, the detailed underlying signaling mechanisms in human microvascular endothelial cells (HMECs) and immune cells need to be clarified in more detail. In this study, we compared the immune stimulatory effects and concomitant intracellular and extracellular signaling mechanisms of immunoglobulin G (IgG)-fractions from kidney transplant patients with allograft vasculopathy (KTx-IgG), to that from patients without vasculopathy, or matched healthy controls (Con-IgG). We found that KTx-IgG from patients with vasculopathy, but not KTx-IgG from patients without vasculopathy or Con-IgG, elicits HMEC activation and subsequent upregulation and secretion of tumor necrosis factor alpha (TNF-α) from HMECs, which was amplified in the presence of the protease-activated thrombin receptor 1 (PAR1) activator thrombin, but could be omitted by selectively blocking the PAR1 receptor. The amount and activity of the TNF-α secreted by HMECs stimulated with KTx-IgG from patients with vasculopathy was sufficient to induce subsequent THP-1 monocytic cell activation. Furthermore, AP-1/c-FOS, was identified as crucial transcription factor complex controlling the KTx-IgG-induced endothelial TNF-α synthesis, and mircoRNA-let-7f-5p as a regulatory element in modulating the underlying signaling cascade. In conclusion, exposure of HMECs to KTx-IgG from patients with allograft vasculopathy, but not KTx-IgG from patients without vasculopathy or healthy Con-IgG, triggers signaling through the PAR1-AP-1/c-FOS-miRNA-let7-axis, to control TNF-α gene transcription and TNF-α-induced monocyte activation. These observations offer a greater mechanistic understanding of endothelial cells and subsequent immune cell activation in the clinical setting of transplant vasculopathy that can eventually lead to transplant failure, irrespective of alloantigen-directed responses.

show abstract

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

Cited by 8 publications

References 42 publications

Pathogenesis of vasculopathy in systemic sclerosis and its contribution to fibrosis

Pathogenesis of vasculopathy in systemic sclerosis and its contribution to fibrosis

Intensive receptor blockade and plasma exchange to treat refractory scleroderma renal crisis in patients with agonistic autoantibodies targeting the angiotensin II type 1 and endothelin-1 type A receptors

Autoantibodies from patients with kidney allograft vasculopathy stimulate a proinflammatory switch in endothelial cells and monocytes mediated via GPCR-directed PAR1-TNF-α signaling

Contact Info

Product

Resources

About