Regulation of the renin-angiotensin system (RAS) in BeWo and HTR-8/SVneo trophoblast cell lines.

Objectives: The renin-angiotensin system (RAS) is implicated in placentation. We determined which RAS pathways are present in two trophoblast cell lines (HTR-8/SVneo and BeWo cells) and the effects of cAMP, which stimulates renal renin.

Study Design: The effect of cAMP on RAS gene expression and on prorenin and angiotensin peptides in HTR-8/SVneo and BeWo cells were investigated.

Results: In HTR-8/SVneo cells, prorenin mRNA (REN) and protein, (pro)renin receptor (ATP6AP2) and angiotensin II type 1 receptor (AGTR1) were stimulated by cAMP (P < 0.05, P < 0.05, P < 0.001 and P < 0.05, respectively). HTR-8/SVneo cells also expressed angiotensinogen (AGT) and angiotensin converting enzyme 1 (ACE1), but did not express AGTR2 or ACE2 nor the Ang 1-7 receptor (MAS1). BeWo cells did not express REN, and REN was not inducible by cAMP, but cAMP increased ACE2 and MAS1 (both P < 0.05) and decreased AGT (P < 0.05). BeWo cells expressed AGT, ACE1, ACE2 and MAS1 but not ATP6AP2, AGTR1 nor AGTR2. There was net destruction of Ang II in media from HTR-8/SVneo and BeWo incubations and net production of Ang 1-7 by BeWo and untreated HTR-8/SVneo cells.

Conclusion: HTR-8/SVneo cells express REN and produce prorenin as well as expressing other RAS genes likely to regulate Ang II/AT(1)R interactions and respond to cAMP, like renal renin-secreting cells. They are more similar to early gestation placentae and are therefore useful for studying effects of renin/ACE/Ang II/AT₁R on cell function. BeWo cells express the ACE2/Ang 1-7/Mas pathway, which is sensitive to cAMP and therefore are useful for studying the effects of ACE2/Ang 1-7/Mas on trophoblast function.