Non-HLA antibodies targeting angiotensin II Type 1 receptor and endothelin-1 Type A receptors induce endothelial injury via ß2-arrestin link to mTOR pathway.
Kidney Int
; 101(3): 498-509, 2022 03.
Article
em En
| MEDLINE
| ID: mdl-34757123
ABSTRACT
Functional non-HLA antibodies (antibodies to non-human leukocyte antigens) targeting the G protein-coupled receptors angiotensin II type 1 receptor (AT1R) and endothelin-1 type A receptor (ETAR) are implicated in the pathogenesis of transplant vasculopathy. While ERK signaling (a regulator of cell growth) may represent a general cellular response to agonist stimulation, the molecular link between receptor stimulation and development of vascular obliteration has not been fully established. Here we hypothesize involvement of the versatile adaptor proteins, ß-arrestins, and the major regulator of cell growth, PI3K/mTOR signaling, in impaired endothelial repair. To test this, human microvascular endothelial cells were treated with AT1R/ETAR antibodies isolated from patients with kidney transplant vasculopathy. These antibodies activated both mTOR complexes via AT1R and ETAR in a PI3K-dependent and ERK-independent manner. The mTOR inhibitor, rapamycin, completely abolished activation of mTORC1 and mTORC2 after long-term treatment with receptor antibodies. Imaging studies revealed that ß2- but not ß1-arrestin was recruited to ETAR in response to ET-1 and patient antibodies but not with antibodies isolated from healthy individuals. Silencing of ß2-arrestin by siRNA transfection significantly reduced ERK1/2 and mTORC2 activation. Non-HLA antibodies impaired endothelial repair by AT1R- and ETAR-induced mTORC2 signaling. Thus, we provide evidence that functional AT1R/ETAR antibodies induce ERK1/2 and mTOR signaling involving ß2-arrestin in human microvascular endothelium. Hence, our data may provide a translational rationale for mTOR inhibitors in combination with receptor blockers in patients with non-HLA receptor recognizing antibodies.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Endotelina-1
/
Receptor Tipo 1 de Angiotensina
Limite:
Humans
Idioma:
En
Revista:
Kidney Int
Ano de publicação:
2022
Tipo de documento:
Article