Antibodies against Angiotensin II Type 1 and Endothelin A Receptors: Relevance and pathogenicity

Abstract

Antibodies against two G-protein coupled receptors (GPCRs), angiotensin II type 1 receptor (AT1R) and endothelin A receptor (ETAR) are among a growing number of autoantibodies that are found to be associated with allograft dysfunction. AT1R antibodies (AT1Rabs) and ETAR antibodies (ETARabs) have been shown to activate their target receptors and affect signaling pathways. Multiple single center reports have shown an association between presence of these antibodies and acute or chronic rejection and graft loss in kidney, heart, liver, lung and composite tissue transplantations. However, the characteristics of patients that are most likely to develop adverse outcomes, the phenotypes associated with graft damage solely due to these antibodies, and the antibody titer required to cause dysfunction are areas that remain controversial. This review compiles existing knowledge on the effect of antibodies against GPCRs in other diseases in order to bridge the gap in knowledge within transplantation biology. Future areas for research are highlighted and include the need for functional assays and treatment protocols for transplant patients who present with AT1Rabs and ETARabs. Understanding how antibodies that activate GPCRs influence transplantation outcome will have direct clinical implications for preemptive evaluation of transplant candidates as well as the post-transplant care of organ recipients.

Keywords: Allograft dysfunction; Angiotensin II type 1 receptor antibody; Endothelin A receptor antibody; Non-HLA antibodies.

Fig. 1.

Angiotensin II type 1 receptor function in homeostasis and dysregulation: AT1R is widely distributed among many tissues and cells and mediates biological effects that maintain normal cellular homeostasis. The Good - AT1R activation by angiotensin II (Ang II) leads to contraction of vascular smooth muscles, accelerates the release of aldosterone and causes sodium retention, which all contribute to blood pressure regulation. Furthermore, AT1R activation leads to increased expression of collagen, proliferation and thickening of cells, and regulates cellular migration. These processes are important in tissue repair. The Bad - when over-activated, either due to increase presence of the natural ligand, Ang II or development of the autoantibody, AT1Rab, the receptor is associated with hypertension and development of fibrosis. AT1Rabs were shown to bind to the receptor and cause phosphorylation of ERK and activation of downstream signaling cascades. Activation of ERK pathways by AT1Rab binding to AT1R leads to an increase in vasoconstriction of arteries and increase in cell migration. The Ugly - AT1Rabs cause a more sustained activation of AT1R as compared to Ang II. These antibodies have been detected in patients with autoimmune diseases, preeclampsia and older individuals; conditions associated with progression of fibrosis, vascular constriction, and increased cellular migration. These same mechanisms may contribute to injury, rejection and graft loss in transplantation.

Fig. 2.

AT1R and ETAR expression from a group of 65 renal transplant recipients. AT1R and ETAR transcripts from patients that received renal transplants were measured by quantitative polymerase chain reaction (qPCR). The patients included in this cohort received a living donor transplant and immunosuppression that consisted of Tacrolimus, Mycophenolate Mofetil and Prednisone. Patients had no delayed graft function, BK viremia nor acute rejection. At one year post-transplant, biopsies were examined and scores for inflammation (i), interstitial fibrosis (ci) and transplant glomerulopathy (cg) were compared to AT1R mRNA and ETAR mRNA expression. Patients were classified based on histopathological examination as normal (n = 25; i/cg/ct = 0); interstitial fibrosis only (n = 24; i/cg = 0; ci > 1) and interstitial fibrosis and inflammation (n = 16; i/cg/ct > 1). (A) AT1R mRNA was higher in patients with interstitial fibrosis but levels decreased in those with both interstitial fibrosis and inflammation. (B) Conversely, ETAR mRNA expression is lower in patients with interstitial fibrosis and increased while AT1R mRNA decreases in patients with interstitial fibrosis and inflammation (3B).