title: Prorenin uptake in the heart: a prerequisite for local angiotensin generation?
abstract: Interference with locally generated angiotensin II most likely underlies the beneficial effects of renin-angiotensin system blockers in cardiac disorders. Since renin is not synthesized in the heart, this enzyme must be sequestered from the circulation in order to allow angiotensin generation at cardiac tissue sites. This review addresses the various ways through which circulating (i.e., kidney-derived) renin may reach cardiac tissue sites, considering in particular the possibility that prorenin, the inactive precursor of renin, is involved in cardiac angiotensin generation, as the plasma concentrations of prorenin are tenfold higher than those of renin. Renin and prorenin diffuse into the cardiac interstitial space and bind to cardiac (pro)renin receptors/renin-binding proteins. One of these receptors is the mannose 6-phosphate/insulin-like growth factor II receptor. This receptor not only binds mannose 6-phosphate-containing ligands like renin and prorenin, it also internalizes these enzymes, and activates prorenin intracellularly. This process possibly represents (pro)renin clearance, since intracellular angiotensin generation could not be demonstrated following (pro)renin uptake by cardiomyocytes. Angiotensin II-mediated myocyte proliferation did occur when incubating cardiomyocytes with prorenin plus angiotensionogen. The effects of prorenin plus angiotensinogen were comparable to those of 100nmol/l angiotensin II, although the angiotensin II levels in the medium during exposure of the cells to prorenin plus angiotensinogen were <1nmol/l. This suggests that cardiac angiotensin II generation by circulating renin occurs predominantly on the cell surface. The presence of ACE and/or renin on the cell membrane, in the microenvironment of angiotensin receptors, would allow maximal efficiency of local angiotensin II generation, i.e., immediate binding of angiotensin II to its receptors with minimal loss into the extracellular space.
authors.affiliation: Department of Pharmacology, Erasmus MC, Rotterdam, The Netherlands. danser@farma.fgg.eur.nl
authors.forename: A H
authors.initials: AH
authors.lastname: Jan Danser
authors.forename: Jasper J
authors.initials: JJ
authors.lastname: Saris
mesh_terms: D000809:Angiotensins / Q000096:biosynthesis*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004058:Diffusion; D004792:Enzyme Precursors / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008322:Mammals / Q000378:metabolism; D008954:Models, Biological; D009124:Muscle Proteins / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009928:Organ Specificity; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D012083:Renin / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology; D025262:Vacuolar Proton-Translocating ATPases; D000093342:Prorenin Receptor
chemical_list: D000809:Angiotensins; D004792:Enzyme Precursors; D009124:Muscle Proteins; D007703:Peptidyl-Dipeptidase A; D017527:Receptor, IGF Type 2; D011956:Receptors, Cell Surface; D012083:Renin; D025262:Vacuolar Proton-Translocating ATPases; C458319:ATP6AP2 protein, human; D000093342:Prorenin Receptor