Is angiotensin II made inside or outside of the cell?

Angiotensin synthesis at tissue sites is well-established, and depends largely, if not completely, on kidney-derived renin. The exact tissue site of angiotensin generation (extracellular fluid, cell surface, intracellular compartment) is still being debated. In this review, we discuss the various possibilities, taking into consideration the intracellular occurrence/absence of prorenin, renin, angiotensinogen, angiotensin-converting enzyme, and angiotensin receptors; the local activation of prorenin to renin; the differences between in vivo and in vitro studies; and the methodologic difficulties related to angiotensin measurements. It is eventually concluded that angiotensin generation at tissue sites occurs extracellularly, most likely on the cell surface.