title: Expression and functional role of the prorenin receptor in the human adrenocortical zona glomerulosa and in primary aldosteronism.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors: 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.
authors: Chiara
authors: C
authors: Recarti
authors: Teresa Maria
authors: TM
authors: Seccia
authors: Brasilina
authors: B
authors: Caroccia
authors: Abril
authors: A
authors: Gonzales-Campos
authors: Giulio
authors: G
authors: Ceolotto
authors: Livia
authors: L
authors: Lenzini
authors: Lucia
authors: L
authors: Petrelli
authors: Anna Sandra
authors: AS
authors: Belloni
authors: William E
authors: WE
authors: Rainey
authors: Juerg
authors: J
authors: Nussberger
authors: Gian Paolo
authors: GP
authors: Rossi
mesh_terms: D000236:Adenoma / Q000378:metabolism*; D000306:Adrenal Cortex Neoplasms / Q000378:metabolism*; D000311:Adrenal Glands / Q000378:metabolism; D000328:Adult; D000450:Aldosterone / Q000096:biosynthesis; D000818:Animals; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D019405:Cytochrome P-450 CYP11B2 / Q000378:metabolism; D005260:Female; D006801:Humans; D006929:Hyperaldosteronism / Q000097:blood* / Q000209:etiology; D006973:Hypertension / Q000097:blood; D020935:MAP Kinase Signaling System; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000097:blood* / Q000235:genetics; D012083:Renin / Q000378:metabolism; D015384:Zona Glomerulosa / Q000378:metabolism*; D000093342:Prorenin Receptor
chemical_list: D011956:Receptors, Cell Surface; D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2; D012083:Renin; D000093342:Prorenin Receptor