Stimulation of endothelin-1 production by autoantibodies present in patients with scleroderma renal crisis

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Wang, Pinchao ; Wu, Dashan ; Gong, Zexian ; Adu-Gyamfi, Michael ; Kamhieh-Milz, Julian ; da Fonseca, Dennyson Leandro Mathias ; Sueruecue, Guelistan ; Ashraf, Muhammad I. ; Heidecke, Harald ; Sikorska, Dorota ; Cabral-Marques, Otavio ; Moll, Guido ; Riemekasten, Gabriela ; Witowski, Janusz ; Catar, Rusan

• Document type: Journal article
• Source: Clinical Immunology; v. 273, p. 10-pg., 2025-02-20.

Abstract

Here, we investigate how autoantibodies against G protein-coupled receptors (GPCRs) on endothelial cells, which are present in patients with scleroderma renal crisis (SRC) impact on endothelin-1 (ET-1) production in human microvascular endothelial cells (HMECs). To this end, serum IgG fraction was isolated from SRC patients and applied to HMECs in culture. Compared to cells treated with either plain control medium or serum IgG from healthy individuals, exposure of HMECs to SRC-IgG resulted in a time- and concentration-dependent increase in ET-1 expression and release. This effect could be blocked by the protease activated receptor 1 (PAR1) inhibitor and mimicked by thrombin, the PAR1 activator. Transcription factor C-FOS/AP-1 and tissue factor (TF) were identified as mediators of these responses. Thus, it can be concluded that serum IgG fraction from SRC patients stimulates endothelial cells to produce ET-1, acting through PAR1 in cooperation with TF. (AU)

• FAPESP's process: 20/07069-0 - Systemic and integrative analysis of T lymphocyte exhaustion mechanisms in patients with COVID-19
• Grantee: Otávio Cabral Marques
• Support Opportunities: Regular Research Grants
• FAPESP's process: 20/01688-0 - Systemic and integrative analysis of the immune response to Zika and Dengue viral infections
• Grantee: Otávio Cabral Marques
• Support Opportunities: Scholarships in Brazil - Young Researchers
• FAPESP's process: 18/18886-9 - Systemic and integrative analysis of the immune response to Zika and Dengue viral infections
• Grantee: Otávio Cabral Marques
• Support Opportunities: Research Grants - Young Investigators Grants