lancet-header
Preprints with The Lancet is part of SSRN´s First Look, a place where journals and other research experts identify content of interest prior to publication. These preprint papers are not peer-reviewed and are posted here as part of a 12-month trial. Authors have either opted in at submission to The Lancet family of journals to post their preprints on Preprints with The Lancet, or submitted directly via SSRN. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. These papers should not be used for clinical decision making or reporting of research to a lay audience without indicating that this is preliminary research that has not been peer-reviewed. For more information see the Comment published in The Lancet, or visit The Lancet´s FAQ page, and for any feedback please contact preprints@lancet.com

Treatment of Primary Aldosteronism with mTORC1 Inhibitors

35 Pages Posted: 16 Jan 2019

See all articles by Beckey Trinh

Beckey Trinh

University of Basel

Matthias Hepprich

University of Basel

Matthias J. Betz

University of Basel

Thilo Burkard

University of Basel - University Hospital Basel

Claudia Cavelti Weder

University of Basel

Eleonora Seelig

University of Basel

Fabian Meienberg

Kantonsspital Baselland

Denise V. Kratschmar

University of Basel

Felix Beuschlein

University Hospital Zurich

Martin Reincke

Klinikum der Universität München

Alex Odermatt

University of Basel

Michael N. Hall

University of Basel - Biozentrum

Marc Donath

University of Basel - Department of Biomedicine; University of Basel - Department of Endocrinology, Diabetes and Metabolism

Marta M. Swierczynska

University of Basel

More...

Abstract

Primary aldosteronism is the most frequent cause of endocrine hypertension. It is characterized by inappropriately high and relatively autonomous aldosterone production by the adrenal cortex Treatment of primary aldosteronism by unilateral adrenalectomy or mineralocorticoid receptor antagonists is not always well tolerated, and targeted pharmacological aldosterone-lowering therapies are still lacking. The adrenal cortex of patients with primary aldosteronism commonly shows increased mTORC1 activity, and mTORC1 inhibition decreases aldosterone production in adrenocortical cells. Here, we show that treatment of mice with rapamycin decreases plasma aldosterone levels, without affecting other steroid hormones. Furthermore, treatment of patients affected by primary aldosteronism with everolimus significantly decreased blood pressure and increased renin levels along with a reduction in aldosterone levels in a subset of patients. These findings suggest a role of mTORC1 in primary aldosteronism and that a subset of patients with this condition may benefit from drugs targeting the mTORC1 pathway.

Clinical Trial Number: The trial was registered at Clinicaltrials.gov (NCT03174171)

Funding Statement: M.N.H. and M.M.S. received funding from Novartis Foundation for Medical Biological Research, M.M.S. received funding from Novartis/University of Basel Excellence Scholarship for Life Sciences. A.O. received funding from the Swiss National Science Foundation (31003A179400). FB and MR have been supported by the Deutsche Forschungsgemeinschaft (DFG) within the CRC/Transregio 205/1 “The Adrenal: Central Relay in Health and Disease“ and by the Else Kröner-Fresenius Stiftung (2013_A182 and 2015_A171 to MR).

Declaration of Interests: The authors declare no competing interests.

Ethics Approval Statement: The study was approved by the regional ethical committee (EKNZ 2015-400) and Swissmedic (2017DR2062), and was conducted in accordance with the guidelines for Good Clinical Practice and the Declaration of Helsinki. All animal experiments were approved by the Kantonales Veterinäramt of Kanton Basel-Stadt (Basel, Switzerland).

Keywords: primary aldosteronism, renin-angiotensin-aldosterone system, mTORC1 inhibitor, rapamycin, everolimus, adrenal cortex hormones, secondary hypertension

Suggested Citation

Trinh, Beckey and Hepprich, Matthias and Betz, Matthias J. and Burkard, Thilo and Cavelti Weder, Claudia and Seelig, Eleonora and Meienberg, Fabian and Kratschmar, Denise V. and Beuschlein, Felix and Reincke, Martin and Odermatt, Alex and Hall, Michael N. and Donath, Marc and Swierczynska, Marta M., Treatment of Primary Aldosteronism with mTORC1 Inhibitors (January 13, 2019). Available at SSRN: https://ssrn.com/abstract=3315815

Beckey Trinh

University of Basel

Petersplatz 1
Basel, CH-4003
Switzerland

Matthias Hepprich

University of Basel

Petersplatz 1
Basel, CH-4003
Switzerland

Matthias J. Betz

University of Basel

Petersplatz 1
Basel, CH-4003
Switzerland

Thilo Burkard

University of Basel - University Hospital Basel

Wilhelm-Klein-Strasse 27
Basel, 4025
Switzerland

Claudia Cavelti Weder

University of Basel

Petersplatz 1
Basel, CH-4003
Switzerland

Eleonora Seelig

University of Basel

Petersplatz 1
Basel, CH-4003
Switzerland

Fabian Meienberg

Kantonsspital Baselland

Liestal, 4410
Switzerland

Denise V. Kratschmar

University of Basel

Petersplatz 1
Basel, CH-4003
Switzerland

Felix Beuschlein

University Hospital Zurich

Rämistrasse 100
8091 Zürich
Switzerland

Martin Reincke

Klinikum der Universität München

Munich, 80336
Germany

Alex Odermatt

University of Basel

Petersplatz 1
Basel, CH-4003
Switzerland

Michael N. Hall

University of Basel - Biozentrum

Klingelbergstrasse 50-70
Basel, CH-4056
Switzerland

Marc Donath (Contact Author)

University of Basel - Department of Biomedicine ( email )

Basel, 4031
United States

University of Basel - Department of Endocrinology, Diabetes and Metabolism ( email )

Basel, 4031
Switzerland

Marta M. Swierczynska

University of Basel

Petersplatz 1
Basel, CH-4003
Switzerland

Click here to go to TheLancet.com

Go to TheLancet.com

Paper statistics

Abstract Views
50
Downloads
12