Treatment of Primary Aldosteronism with mTORC1 Inhibitors

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 Kroner-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 Veterinaramt of Kanton Basel-Stadt (Basel, Switzerland).