Periodic Reporting for period 3 - PAPA (Pathophysiology of Primary Aldosteronism)
Berichtszeitraum: 2020-01-01 bis 2021-06-30
It is the first hypothesis of this proposal that the pathophysiology of PA is a process based on two ‘hits’: agonistic angiotensin II type 1 receptor (AT1R) autoantibodies and somatic mutations. Whereas agonistic autoantibodies induce proliferation and grossly changes adrenal cortex architecture towards diffuse or nodular hyperplasia, somatic mutations result in adenoma formation. It is the second hypothesis, that together, both factors induce not only aldosterone but also marked glucocorticoid excess. In the first 2.5 years we have analysed prevalence and binding characteristics of AT1R autoantibodies as a pathophysiologic basis of PA. These data demonstrate that patients with PA displayed different levels of AT1R activation with different responses to inhibition by losartan. Patients with BAH displayed higher losartan-independent affinity-isolated agonistic AT1R-Ab levels compared with patients with APA (P<0.01) and with normotensive individuals (P<0.0001). Taken together these data support our first hypothesis that agonistic AT1R antibodies may have a functional role in a subgroup of patients with PA. We are currently determining the effects of AT1R antibodies and genetic factors on cellular adrenal cortex models in vitro. In the next years we will extend these studies to specific in vivo genetic rodent models of PA. We also have quantified aldosterone and glucocorticoid excess as disease effectors of PA using liquid chromatography–mass spectrometry demonstrating that mineralocorticoid and glucocorticoid signatures can be found in plasma and urine of PA patients, and that these signatures are predictive for underlying somatic driver mutations as well as for metabolic and cardiovascular phenotypes. This is strong evidence for our second hypothesis. In summary, we found compelling evidence in support of the two main hypotheses of our grant.
In summary, within the first 2.5 years we have made exceptional advances in the basic research to elucidate the humoral and molecular mechanisms underlying aldosterone and cortisol excess and hypertension as we were able to identify specific genotype-phenotype signatures of PA via mass spectrometry based liquid biopsies leading to optimized prediction of blood pressure outcomes after treatment (Williams et al., 2017, Yang et al., 2019)
The investigation of the effects of somatic APA mutations on adrenocortical cell growth will be completed by the end of 2019. Transcriptional analysis of resected adrenal samples from patients with unilateral PA will also be used to identify key genes and intracellular signaling pathways mediating deregulated cell growth. The study should be completed and published in 2020.
Based on the successful implementation of the LC-MS measurement of steroid profiles in blood samples as well as the development of statistical models required to interpret the profile data, we expect being able to discover more unique steroid profile finger prints correlated to specific clinical features or subtypes of PA. We also plan to correlate such profiles to the presence of activating AT1R autoantibodies to contribute to the understanding of pathophysiological mechanisms in patients affected by such autoantibodies. Additional analysis of urine samples from our patient cohorts will allow us a deeper understanding of steroid pathways involved in pathophysiology of subtypes of PA in future times.