Journal
PLOS ONE
Volume 10, Issue 11, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0142664
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Funding
- Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Science, ICT and future Planning [2013R1A2A2A01067611]
- Pioneer Research Center Program through the National Research Foundation of Korea - Ministry of Science, ICT & Future Planning [2014M3C1A3053036]
- Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI)
- Ministry of Health & Welfare, Republic of Korea [HI14C2084]
- National Research Foundation of Korea [2014M3C1A3053036] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Background Angiotensin-(1-7) [Ang-(1-7)] counteracts many actions of the renin-angiotensin-aldosterone system. Despite its renoprotective effects, extensive controversy exists regarding the role of Ang-(1-7) in obstructive nephropathy, which is characterized by renal tubulointerstitial fibrosis and apoptosis. Methods To examine the effects of Ang-(1-7) in unilateral ureteral obstruction (UUO), male Sprague-Dawley rats were divided into three groups: control, UUO, and Ang-(1-7)-treated UUO rats. Ang-(1-7) was continuously infused (24 mu g/[kg.h]) using osmotic pumps. We also treated NRK-52E cells in vitro with Ang II (1 mu M) in the presence or absence of Ang-(1-7) (1 mu M), Mas receptor antagonist A779 (1 mu M), and Mas receptor siRNA (50 nM) to examine the effects of Ang-(1-7) treatment on Ang II-stimulated renal injury via Mas receptor. Results Angiotensin II (Ang II) and angiotensin type 1 receptor (AT(1)R) protein expression was higher in UUO kidneys than in controls. Ang-(1-7) treatment also decreased proapoptotic protein expression in UUO kidneys. Ang-(1-7) also significantly ameliorated TUNEL positive cells in UUO kidneys. Additionally, Ang-(1-7) reduced profibrotic protein expression and decreased the increased tumor growth factor (TGF)-beta 1/Smad signaling present in UUO kidneys. In NRK-52E cells, Ang II induced the expression of TGF-beta 1/Smad signaling effectors and proapoptotic and fibrotic proteins, as well as cell cycle arrest, which were attenuated by Ang-(1-7) pretreatment. However, treatment with A779 and Mas receptor siRNA enhanced Ang II-induced apoptosis and fibrosis. Moreover, Ang II increased tumor necrosis factor-alpha converting enzyme (TACE) and decreased angiotensin-converting enzyme 2 (ACE2) expression in NRK-52E cells, while pretreatment with Ang-(1-7) or A779 significantly inhibited or enhanced these effects, respectively. Conclusion Ang-(1-7) prevents obstructive nephropathy by suppressing renal apoptosis and fibrosis, possibly by regulating TGF-beta 1/Smad signaling and cell cycle arrest via suppression of AT(1)R expression. In addition, Ang-(1-7) increased and decreased ACE2 and TACE expression, respectively, which could potentially mediate a positive feedback mechanism via the Mas receptor.
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