title: Aliskiren binds to renin and prorenin bound to (pro)renin receptor in vitro.
abstract: Human (pro)renin receptor ((P)RR) has been implicated in the augmentation of many biological and cellular processes through bindings to its ligands, renin and prorenin. In this study, we investigated the effects of aliskiren, a direct oral renin inhibitor, on the activities of free and (P)RR-bound forms of human mature renin. We also elucidated the effect of aliskiren on the 'renin activity' of the receptor-bound form of prorenin. Aliskiren had an IC(50) of 0.72 nmol l(-1) against renin. The compound competitively inhibited renin activity with an inhibitory constant (K(i)) of 0.18 nmol  l(-1). Furthermore, the dissociation constants (K(D)) for aliskiren from renin and prorenin bound to (P)RR were determined using surface plasmon resonance in a BIAcore assay system (Uppsala, Sweden). These values were estimated to be 0.46 ± 0.03 and 0.25 ± 0.01 nmol  l(-1), respectively. The compound competitively inhibited the renin activities of (P)RR-bound forms of both renin and prorenin with a K(i) of 0.14 and 0.15 nmol  l(-1), respectively. These results indicate that aliskiren could be a potent inhibitor of the free forms of mature renin and of the receptor-bound forms of renin and prorenin.
authors.affiliation: Laboratory of Animal Biochemistry, United Graduate School of Agricultural Science, Gifu University, Gifu, Japan.
authors.forename: Kazal Boron
authors.initials: KB
authors.lastname: Biswas
authors.forename: A H M Nurun
authors.initials: AH
authors.lastname: Nabi
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Arai
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Akio
authors.initials: A
authors.lastname: Ebihara
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Ichihara
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Tadashi
authors.initials: T
authors.lastname: Inagami
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Suzuki
mesh_terms: D000577:Amides / Q000378:metabolism* / Q000494:pharmacology; D005650:Fumarates / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D012083:Renin / Q000378:metabolism*; D013997:Time Factors; D025262:Vacuolar Proton-Translocating ATPases / Q000187:drug effects / Q000378:metabolism*; D000093342:Prorenin Receptor; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D005650:Fumarates; D008024:Ligands; D011956:Receptors, Cell Surface; D012083:Renin; D025262:Vacuolar Proton-Translocating ATPases; D000093342:Prorenin Receptor; D000092502:Renin Inhibitors; C458319:ATP6AP2 protein, human; C446481:aliskiren