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The (pro)renin receptor ((P)RR), which is a recently discovered molecule of the renin-angiotensin system, plays an important role in the development of cardiovascular diseases. However, the molecular properties and the subcellular distribution of (P)RR remain controversial. In this study, (P)RR-Venus in Chinese hamster ovary (CHO) cells ((P)RR-Venus-CHO) or endogenous (P)RR in human vascular smooth muscle cells (VSMC) were constitutively cleaved without any stimulation, and secretion of the amino-terminal fragment (NTF-(P)RR) into the media was determined using western blot analysis. Immunofluorescent analysis showed robust expression of (P)RR in the endoplasmic reticulum (ER) or the Golgi but not in the plasma membrane. Moreover, we identified ADAM19, which is expressed in the Golgi, as one of cleaving proteases of (P)RR. Transfected ADAM19 evoked the shedding of (P)RR, whereas transfected dominant negative ADAM19 suppressed it. Although (P)RR contains a furin cleavage site, neither the furin-deficient LoVo cells nor furin inhibitor-treated VSMC lost NTF-(P)RR in the media. The secreted NTF-(P)RR induced the renin activity of prorenin in the extracellular space. We describe that (P)RR is mainly localized in the subcellular organelles, such as the ER and Golgi, and (P)RR is cleaved by ADAM19 in the Golgi resulting in two fragments, NTF-(P)RR and CTF-(P)RR. These results may suggest that (P)RR is predominantly secreted into the extracellular space.

The (pro)renin receptor is cleaved by ADAM19 in the Golgi leading to its secretion into extracellular space