Angiotensin-(1–7) inhibits angiotensin II-stimulated phosphorylation of MAP kinases in proximal tubular cells

Su, Z.; Zimpelmann, J.; Burns, K. D.
June 2006
Kidney International;Jun2006, Vol. 69 Issue 12, p2212
Academic Journal
Angiotensin-converting enzyme 2 (ACE2) is a homolog of ACE, which is not blocked by ACE inhibitors. High amounts of ACE2 are present in the proximal tubule, and ACE2 catalyzes generation of angiotensin 1–7 (Ang-(1–7)) by this segment. Ang-(1–7) binds to a receptor distinct from the AT1 or AT2 Ang II receptor, identified as the mas receptor. We studied the effects of Ang-(1–7) on Ang II-mediated cell signaling pathways in proximal tubule. In primary cultures of rat proximal tubular cells, activation of mitogen-activated protein kinases (MAPK) was detected by immunoblotting, in the presence or absence of agonists/antagonists. Transforming growth factor-β1 (TGF-β1) was measured by enzyme-linked immunosorbent assay. Ang II (5 min, 10−7 M) stimulated phosphorylation of the three MAPK (p38, extracellular signal-related kinase (ERK 1/2), and c-Jun N-terminal kinase (JNK)). While incubation of proximal tubular cells with Ang-(1–7) alone did not significantly affect MAPK phosphorylation, Ang-(1–7) (10−7 M) completely inhibited Ang II-stimulated phosphorylation of p38, ERK 1/2, and JNK. This inhibitory effect was reversed by the Ang-(1–7) receptor antagonist, D-Ala7-Ang-(1–7). Ang II significantly increased production of TGF-β1 in proximal tubular cells, an effect that was partly inhibited by Ang-(1–7). Ang-(1–7) had no significant effect on cyclic 3′,5′-adenosine monophosphate production in these cells. In summary, Ang-(1–7) inhibits Ang II-stimulated MAPK phosphorylation in proximal tubular cells. Generation of Ang-(1–7) by proximal tubular ACE2 could thereby serve a protective role by counteracting the effects of locally generated Ang II.Kidney International (2006) 69, 2212–2218. doi:10.1038/sj.ki.5001509; published online 3 May 2006


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