title: Aliskiren inhibits the renin-angiotensin system in retinal pigment epithelium cells.
abstract: Observations of increased angiotensin II levels and activation of the (pro)renin receptor in retinopathies support the role of ocular renin-angiotensin system (RAS) in the development of retinal diseases. While targeting RAS presents significant therapeutic potential, current RAS-based therapies are ineffective halting the progression of these diseases. A new class of drugs, the direct renin inhibitors such as aliskiren, is a potential therapeutic alternative. However, it is unclear how aliskiren acts in the retina, in particular in the retinal pigment epithelium (RPE), the structure responsible for the maintenance of retinal homeostasis whose role is deeply compromised in retinal diseases. We firstly analyzed the expression and activity of the main RAS components in RPE cells. Time- and concentration-dependent treatments with aliskiren were performed to modulate different pathways of the RAS in RPE cells. Our data demonstrate that RPE cells express the main RAS constituents. Exposure of RPE cells to aliskiren inhibited the activity of renin and consequently decreased the levels of angiotensin II. Additionally, aliskiren reduced the translocation of the (pro)renin receptor to the cellular membrane of RPE cells preventing the activation of ERK1/2. Our findings of the RPE well-defined RAS, together with the demonstration that aliskiren effectively blocks this system at different steps of the cascade, suggest that aliskiren might be an alternative and successful drug in preventing the deleterious effects derived from the overactivation of the RAS, known to contribute to the pathogenesis of different retinal diseases.
authors.affiliation: Centre for Biomedical Research (CBMR), University of Algarve, Campus Gambelas, 8005-139 Faro, Portugal; CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo Mártires da Pátria 130, 1169-056 Lisboa, Portugal. Electronic address: sgsimao@ualg.pt.
authors.forename: Sónia
authors.initials: S
authors.lastname: Simão
authors.affiliation: ProRegeM PhD Program, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo Mártires da Pátria 130, 1169-056 Lisboa, Portugal. Electronic address: daniela.filipa.santos@nms.unl.pt.
authors.forename: Daniela F
authors.initials: DF
authors.lastname: Santos
authors.affiliation: CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo Mártires da Pátria 130, 1169-056 Lisboa, Portugal. Electronic address: gabriela.silva@nms.unl.pt.
authors.forename: Gabriela A
authors.initials: GA
authors.lastname: Silva
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000804:Angiotensin II / Q000378:metabolism; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002460:Cell Line; D005650:Fumarates / Q000494:pharmacology*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D011956:Receptors, Cell Surface / Q000378:metabolism; D012083:Renin / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects*; D055213:Retinal Pigment Epithelium / Q000166:cytology*; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism; D000093342:Prorenin Receptor
chemical_list: D000577:Amides; D000804:Angiotensin II; D000959:Antihypertensive Agents; D005650:Fumarates; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D011956:Receptors, Cell Surface; D012083:Renin; D025262:Vacuolar Proton-Translocating ATPases; C458319:ATP6AP2 protein, human; D000093342:Prorenin Receptor; C446481:aliskiren
keywords: Aliskiren; Prorenin receptor; Renin-angiotensin system; Retinal pigment epithelium cells