Project B14

Genetic and environmental contributors to vascular function in primary aldosteronism

Principal Investigators

Prof. Dr. rer. nat.
Michael Mederos y Schnitzler

LMU München,

Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine,

mederos[at]lrz.uni-muenchen.de

Dr. med.
Holger Schneider

LMU Klinikum München,

Department of Internal Medicine IV, Endocrinology,

holger.schneider[at]med.uni-muenchen.de

Prof. Dr. med.
Felix Beuschlein

LMU Klinikum München,

Department of Internal Medicine IV, Endocrinology,

Universitätsspital Zürich,

felix.beuschlein[at]usz.ch

Prof. Dr. med. Thomas Gudermann
LMU München, Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Thomas.gudermann[at]lrz.uni-muenchen.de

Scientific Staff

Twinkle Vohra – Postdoc
Moaz Alkaboni – PhD student
Michaela Höhne – TA

Project Description

The causes of the excessive cardiovascular morbidity in patients with primary aldosteronism (PA) are ill-defined, but likely involve both genetic and environmental factors that modulate both aldosterone secretion and its harmful actions on target tissues. Clinical studies suggest that dietary salt and fat intake are relevant environmental contributors. It is still unknown whether these factors simply aggravate the detrimental effects of aldosterone on vascular structure and function or whether adrenal steroid hypersecretion is further exacerbated by diet.

In the second funding period, we therefore aim at a more granular understanding of the processes which govern vascular remodeling in PA and at defining innovative routes to therapy. Therapeutic advances would very likely be applicable to essential hypertension and, thus, carry a tremendous public health impact.

Specifically, we aim at characterising the interactions between dietary environmental stressors and endogenous hyperaldosteronism. A particular focus will be placed on adrenal as well as cardiovascular effects. We strive to develop pathophysiology-guided therapies to simultaneously address adrenal oversecretion and cardiovascular maladaptive responses.

Aims

(I) Determine the combined impact of mineralocorticoid excess and dietary stress on cardiovascular and adrenal function on a tissue level.

(II) Identify adrenal and vascular cell types affected by aldosterone and environmental stressors.

(III) Establish the utility of novel therapeutic molecular mechanisms addressing tissue-protective mechanosensitive vascular reflexes and normalising adrenal mineralocorticoid output in diet-augmented endogenous hyperaldosteronism.

Publications

Brunnenkant L, Meng Y, Sun J, Gonzalez Marques J, Koletzko B, Mederos y Schnitzler M, Gudermann T, Williams TA, Beuschlein F, Heinrich DA, Adolf C, Reincke M, Schneider H. The epoxyeicosatrienoic pathway is intact in endothelial and smooth muscle cells exposed to aldosterone excess. bioRxiv 2021.

Erdogmus S, Storch U, Danner L, Becker J, Winter M, Ziegler N, Wirth A, Offermanns S, Hoffmann C, Gudermann T, Mederos y Schnitzler M. Helix 8 is the essential structural motif of mechanosensitive GPCRs. Nat Commun 2019; 10:5784

Murakami M, Rhayem Y, Kunzke T, Sun N, Feuchtinger A, Ludwig P, Strom TM, Gomez-Sanchez C, Knösel T, Kirchner T, Williams TA, Reincke M, Walch AK, Beuschlein F. In situ metabolomics of aldosterone-producing adenomas. JCI Insight 2019; 4:e130356

Yang Y, Gomez-Sanchez CE, Jaquin D, Aristizabal Prada ET, Meyer LS, Knosel T, Schneider H, Beuschlein F, Reincke M, Williams TA. Primary Aldosteronism: KCNJ5 Mutations and Adrenocortical Cell Growth. Hypertension 2019; 74:809-816

Heinrich DA, Adolf C, Holler F, Lechner B, Schneider H, Riester A, Nirschl N, Sturm L, Wang X, Ladurner R, Seidensticker M, Bidlingmaier M, Beuschlein F, Reincke M. Adrenal Insufficiency After Unilateral Adrenalectomy in Primary Aldosteronism: Long-Term Outcome and Clinical Impact. J Clin Endocrinol Metab 2019; 104:5658-5664

Perez-Rivas LG, Rhayem Y, Sabrautzki S, Hantel C, Rathkolb B, Hrabe de Angelis M, Reincke M, Beuschlein F, Spyroglou A. Genetic characterization of a mouse line with primary aldosteronism. J Mol Endocrinol 2017; 58:67-78

Schubert KM, Qiu J, Blodow S, Wiedenmann M, Lubomirov LT, Pfitzer G, Pohl U, Schneider H. The AMP-Related Kinase (AMPK) Induces Ca(2+)-Independent Dilation of Resistance Arteries by Interfering With Actin Filament Formation. Circ Res 2017; 121:149-161

Kirsch J, Schneider H, Pagel JI, Rehberg M, Singer M, Hellfritsch J, Chillo O, Schubert KM, Qiu J, Pogoda K, Kameritsch P, Uhl B, Pircher J, Deindl E, Muller S, Kirchner T, Pohl U, Conrad M, Beck H. Endothelial Dysfunction, and A Prothrombotic, Proinflammatory Phenotype Is Caused by Loss of Mitochondrial Thioredoxin Reductase in Endothelium. Arterioscler Thromb Vasc Biol 2016; 36:1891-1899