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Expression and functional role of the prorenin receptor in the human adrenocortical zona glomerulosa and in primary aldosteronism

Recarti, Chiaraa,b,*; Seccia, Teresa Mariaa,*; Caroccia, Brasilinaa; Gonzales-Campos, Abrila; Ceolotto, Giulioa; Lenzini, Liviaa; Petrelli, Luciac; Belloni, Anna Sandrac; Rainey, William E.d; Nussberger, Juerge; Rossi, Gian Paoloa

doi: 10.1097/HJH.0000000000000504
ORIGINAL PAPERS: Pathophysiological aspects
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Objectives: Prorenin can be detected in plasma of hypertensive patients. If detected in patients with primary aldosteronism could implicate prorenin in the development of primary aldosteronism. To address this issue, we measured the plasma prorenin levels in primary aldosteronism patients, the expression of the prorenin receptor (PRR) in the normal human adrenocortical zona glomerulosa and aldosterone-producing adenoma (APA), and we investigated the functional effects of PRR activation in human adrenocortical cells.

Method: Plasma renin activity, aldosterone, and active and total trypsin-activated renin were measured in primary aldosteronism patients, essential hypertensive patients, and healthy individuals, and then prorenin levels were calculated. Localization and functional role of PRR were investigated in human and rat tissues, and aldosterone-producing cells.

Results: Primary aldosteronism patients had detectable plasma levels of prorenin. Using digital-droplet real-time PCR, we found a high PRR-to-porphobilinogen deaminase ratio in both the normal adrenal cortex and APAs. Marked expression of the PRR gene and protein was also found in HAC15 cells. Immunoblotting, confocal, and immunogold electron microscopy demonstrated PRR at the cell membrane and intracellularly. Renin and prorenin significantly triggered both CYP11B2 expression (aldosterone synthase) and ERK1/2 phosphorylation, but only CYP11B2 transcription was prevented by aliskiren.

Conclusion: The presence of detectable plasma prorenin in primary aldosteronism patients, and the high expression of PRR in the normal human adrenal cortex, APA tissue, CD56+ aldosterone-producing cells, along with activation of CYP11B2 synthesis and ERK1/2 phosphorylation, suggest that the circulating and locally produced prorenin may contribute to the development or maintenance of human primary aldosteronism.

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aDepartment of Medicine – DIMED, Padova, Italy

bCARIM - School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands

cDepartment of Molecular Medicine, University of Padova, Padova, Italy

dMolecular & Integrative Physiology, Ann Arbor, University of Michigan, Ann Arbor, Michigan, USA

eDepartment of Internal Medicine – Division of Angiology and Hypertension, University of Lausanne, Switzerland.

*Chiara Recarti and Teresa Maria Seccia contributed equally to the writing of this article.

Correspondence to Professor Gian Paolo Rossi, MD, FACC, FAHA, Department of Medicine – DIMED, Internal Medicine 4, University Hospital, Via Giustiniani, 2, 35126 Padova, Italy.Tel: +39 049 821 2279 or 7821; fax: +39 049 821 7873; e-mail: gianpaolo.rossi@unipd.it

Abbreviations: Ang II, angiotensin II; APA, aldosterone-producing adenoma; BP, blood pressure; Elk, Ets-like gene; MAPK, mitogen-activated protein kinase; PAC, plasma aldosterone concentration; PBGD, porphobilinogen deaminase; PRA, plasma renin activity; PRR, prorenin receptor

Received 27 July, 2014

Revised 28 November, 2014

Accepted 28 November, 2014

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.jhypertension.com).

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