Dataset Information

Cytokine Profiles Associated With Angiotensin II Type 1 Receptor Antibodies.

ABSTRACT: Introduction:Angiotensin II type 1 receptor antibody (AT1R-Ab), is a non-human leukocyte antigen (HLA) antibody implicated in poor renal allograft outcomes, although its actions may be mediated through a different pathway than HLA donor-specific antibodies (DSAs). Our aim was to examine serum cytokine profiles associated with AT1R-Ab and distinguish them from those associated with HLA DSA in serially collected blood samples from a cohort of pediatric renal transplant recipients. Methods:Blood samples from 65 pediatric renal transplant recipients drawn during the first 3 months posttransplant, at 6, 12, and 24 months posttransplant, and during suspected episodes of kidney transplant rejection were tested for AT1R-Ab, HLA DSA, and a panel of 6 cytokines (tumor necrosis factor [TNF]-?, interferon [IFN]-?, interleukin [IL]-8, IL-1?, IL-6, and IL-17). Associations between antibodies and cytokines were evaluated. Results:AT1R-Ab, but not HLA DSA, was associated with elevations in TNF-?, IFN-?, IL-8, IL-1?, IL-6, and IL-17. This relationship remained significant even after controlling for relevant clinical factors and was consistent across all time points. In contrast to HLA DSA, AT1R-Ab was associated with elevations in vascular inflammatory cytokines in the first 2 years posttransplant. Conclusions:This profile of vascular cytokines may be informative for clinical monitoring and designing future studies to delineate the distinct pathophysiology of AT1R-Ab-mediated allograft injury in kidney transplantation.

SUBMITTER: Pearl MH

PROVIDER: S-EPMC6451195 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Cytokine Profiles Associated With Angiotensin II Type 1 Receptor Antibodies.

Pearl Meghan H MH Grotts Jonathan J Rossetti Maura M Zhang Qiuheng Q Gjertson David W DW Weng Patricia P Elashoff David D Reed Elaine F EF Tsai Chambers Eileen E

Kidney international reports 20181221 4

<h4>Introduction</h4>Angiotensin II type 1 receptor antibody (AT1R-Ab), is a non-human leukocyte antigen (HLA) antibody implicated in poor renal allograft outcomes, although its actions may be mediated through a different pathway than HLA donor-specific antibodies (DSAs). Our aim was to examine serum cytokine profiles associated with AT1R-Ab and distinguish them from those associated with HLA DSA in serially collected blood samples from a cohort of pediatric renal transplant recipients.<h4>Metho ...[more]

PMID: 30997435

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Project description:The angiotensin II (Ang II) type 1 receptor (AT1R) is involved in the regulation of blood pressure (through vasoconstriction) and water and ion homeostasis (mediated by interaction with the endogenous agonist). AT1R can also be activated by auto-antibodies (AT1R-Abs), which are associated with manifold diseases, such as obliterative vasculopathy, preeclampsia and systemic sclerosis. Knowledge of the molecular mechanisms related to AT1R-Abs binding and associated signaling cascade (dys-)regulation remains fragmentary. The goal of this study was, therefore, to investigate details of the effects of AT1R-Abs on G-protein signaling and subsequent cell proliferation, as well as the putative contribution of the three extracellular receptor loops (ELs) to Abs-AT1R signaling. AT1R-Abs induced nuclear factor of activated T-cells (NFAT) signaling, which reflects Gq/11 and Gi activation. The impact on cell proliferation was tested in different cell systems, as well as activation-triggered receptor internalization. Blockwise alanine substitutions were designed to potentially investigate the role of ELs in AT1R-Abs-mediated effects. First, we demonstrate that Ang II-mediated internalization of AT1R is impeded by binding of AT1R-Abs. Secondly, exclusive AT1R-Abs-induced Gq/11 activation is most significant for NFAT stimulation and mediates cell proliferation. Interestingly, our studies also reveal that ligand-independent, baseline AT1R activation of Gi signaling has, in turn, a negative effect on cell proliferation. Indeed, inhibition of Gi basal activity potentiates proliferation triggered by AT1R-Abs. Finally, although AT1R containing EL1 and EL3 blockwise alanine mutations were not expressed on the human embryonic kidney293T (HEK293T) cell surface, we at least confirmed that parts of EL2 are involved in interactions between AT1R and Abs. This current study thus provides extended insights into the molecular action of AT1R-Abs and associated mechanisms of interrelated pathogenesis.

Project description:The binding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein to its cellular receptor, the angiotensin-converting enzyme 2 (ACE2), causes its downregulation, which subsequently leads to the dysregulation of the renin-angiotensin system (RAS) in favor of the ACE-angiotensin II (Ang II)-angiotensin II type I receptor (AT1R) axis. AT1R has a major role in RAS by being involved in several physiological events including blood pressure control and electrolyte balance. Following SARS-CoV-2 infection, pathogenic episodes generated by the vasoconstriction, proinflammatory, profibrotic, and prooxidative consequences of the Ang II-AT1R axis activation are accompanied by a hyperinflammatory state (cytokine storm) and an acute respiratory distress syndrome (ARDS). AT1R, a member of the G protein-coupled receptor (GPCR) family, modulates Ang II deleterious effects through the activation of multiple downstream signaling pathways, among which are MAP kinases (ERK 1/2, JNK, p38MAPK), receptor tyrosine kinases (PDGF, EGFR, insulin receptor), and nonreceptor tyrosine kinases (Src, JAK/STAT, focal adhesion kinase (FAK)), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. COVID-19 is well known for generating respiratory symptoms, but because ACE2 is expressed in various body tissues, several extrapulmonary pathologies are also manifested, including neurologic disorders, vasculature and myocardial complications, kidney injury, gastrointestinal symptoms, hepatic injury, hyperglycemia, and dermatologic complications. Therefore, the development of drugs based on RAS blockers, such as angiotensin II receptor blockers (ARBs), that inhibit the damaging axis of the RAS cascade may become one of the most promising approaches for the treatment of COVID-19 in the near future. We herein review the general features of AT1R, with a special focus on the receptor-mediated activation of the different downstream signaling pathways leading to specific cellular responses. In addition, we provide the latest insights into the roles of AT1R in COVID-19 outcomes in different systems of the human body, as well as the role of ARBs as tentative pharmacological agents to treat COVID-19.

Dataset Information

Cytokine Profiles Associated With Angiotensin II Type 1 Receptor Antibodies.

Publications

Cytokine Profiles Associated With Angiotensin II Type 1 Receptor Antibodies.

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