Unraveling the Prevalence of Angiotensin II Type 1 Receptor Antibodies in Hypertension

Hypertension is one of the major causes for cardiovascular diseases.1 Excessive blood pressure can trigger damages to the heart or the blood vessels of major organs, such as the brain or the kidneys.2 Furthermore, high blood pressure in the kidney results in major long-time consequences such as renal arteriosclerosis, renal insufficiency, or uremia. Different factors can influence blood pressure, among which antibodies targeting the Angiotensin II type 1 receptor (AT1R), a G-protein-coupled receptor. Antibodies directed against AT1R (AT1R-Abs) were first discovered in women with preeclampsia.3 In these patients, AT1R-Abs acted as agonists of AT1R that increased the beating rate of neonatal rat cardiomyocytes in a bioassay and recognized one epitope located in the second extracellular loop (AT1R ECL2) of the receptor. A specific blocker of AT1R, losartan, could inhibit these effects. Following this study, AT1R-Abs were identified in patients with acute kidney graft rejection and malignant hypertension.4 In this clinical setting, the antibodies targeted AT1R ECL2 similarly, underlining the importance of this structure, and provoked renal lesions in vivo after passive transfer in rats. The importance of AT1R-Abs in organ transplantation led to the development of a new commercial Enzyme-linked immunosorbent assay (ELISA) that could be used in clinical routine and used AT1R in its native conformation (OneLambda, Thermo Fisher). This ELISA was validated in different clinical studies since then.5,6 Recently, AT1R-Abs have been involved in the pathogenesis of primary aldosteronism7–9 suggesting a link between the presence of the antibodies and elevated blood pressure. However, a potential role of AT1R-Abs in essential hypertension is still under investigation. In this issue of American Journal of Hypertension, Philogene et al. investigated the prevalence of AT1R-Abs in hypertension in the participants to the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study.10 This study recruited 3,722 people and aimed at defining how belonging to minorities and low socioeconomic groups influence the development of cardiovascular cerebrovascular diseases.11 One thousand and six participants self-reported hypertension at study baseline. Among these, 13.1% were tested positive in ELISA for the presence of AT1R-Abs with a significantly higher prevalence of Caucasian people and significantly less tobacco-smoking individuals. Although the mean systolic blood pressure and uncontrolled blood pressure were similar between AT1R-Abs positive and negative groups, the mean diastolic blood pressure was significantly higher in AT1R-Abs positive individuals.10 These results corroborate several studies that associated AT1R-Abs to essential hypertension.12–17 Nevertheless, the category and parameters of hypertension studied varied from one work to the other, and it remains controversial whether the immunization against AT1R participates to the development of hypertension or antagonizes it. While a study from 2018 showed that rats vaccinated with a combination of a peptide from AT1R ECL2 with pneumococcal surface protein A showed significantly reduced systolic blood pressure when compared with nonvaccinated animals,16 rabbits immunized with a peptide from AT1R ECL2 presented significantly increased heart rate and mean arterial pressure.17 Hence, complementary studies are still necessary to clarify the influence of AT1R-Abs on hypertension. A major finding of the work of Philogene et al. is that prescription of angiotensin receptor blocker to participants who tested positive for AT1R-Abs resulted in significantly higher systolic blood pressure and some patients presenting uncontrolled blood pressure.10 These results contradict those from the Study of Optimal Treatment in Hypertensive Patients with Anti-AT1R Antibodies (SOT-AT1),15 in which the authors reported that treatment of hypertensive patients with a specific angiotensin receptor blocker, Candesartan, triggered a decrease of systolic blood pressure and diastolic blood pressure that was significantly stronger in the group of AT1R-Abs positive patients. Besides, the SOT-AT1 study showed that hypertensive AT1R-Abs positive patients treated with angiotensin-conversing enzyme inhibitors comparatively required additional hypertensive medication more frequently than a similar group treated with angiotensin receptor blocker.15 The discrepancies between the 2 studies can stem from different reasons. First, the SOT-AT1 study only used Candesartan, whereas participants enrolled in the HANDLS study received different angiotensin receptor blockers.10,15 Moreover, the work of Philogene et al. is the first to use an ELISA with native AT1R to assess the presence of AT1R-Abs10 (current issue), when all other studies published on AT1R-Abs, including SOT-AT1, used peptide-based ELISA.12–17 As antibodies against AT1R appear to be conformation-sensitive, using peptide ELISA may generate false positive or false negative biases and influence the results of the studies. Altogether, the work by Philogene et al. shows that the association between AT1R-Abs and hypertension needs to be further investigated with a careful screening of patients carefully chosen, and that clinical studies should be complemented with functional studies to verify the influence of AT1R-Abs in vivo. Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—Project number 394046635—SFB 1365. The author declared no conflict of interest.