Prorenin is the endogenous agonist of the (pro)renin receptor. Binding kinetics of renin and prorenin in rat vascular smooth muscle cells overexpressing the human (pro)renin receptor.
OBJECTIVE
Mannose 6-phosphate receptors (M6PR) bind both renin and prorenin, and such binding contributes to renin/prorenin clearance but not to angiotensin generation. Here, we evaluated the kinetics of renin/prorenin binding to the recently discovered human (pro)renin receptor (h(P)RR), and the idea that such binding underlies tissue angiotensin generation.


RESULTS
Vascular smooth muscle cells from control rats and transgenic rats with smooth muscle h(P)RR overexpression were incubated at 4 or 37 degrees C with human renin or prorenin. Incubation at 37 degrees C greatly increased binding, suggesting that (pro)renin-binding receptors cycle between the intracellular compartment and the cell surface. Blockade of the M6PR reduced binding by approximately 50%. During M6PR blockade, h(P)RR cells bound twice as much prorenin as control cells, while renin binding was unaltered. Incubation of h(P)RR (but not control) cells with prorenin + angiotensinogen yielded more angiotensin than expected on the basis of the activity of soluble prorenin, whereas angiotensin generation during incubation of both cell types with renin + angiotensinogen was entirely due to soluble renin. The renin + angiotensinogen-induced vasoconstriction of isolated iliac arteries from control and transgenic rats was also due to soluble renin only. The recently proposed (P)RR antagonist 'handle region peptide', which resembles part of the prosegment, blocked neither prorenin binding nor angiotensin generation.


CONCLUSIONS
H(P)RRs preferentially bind prorenin, and such binding results in angiotensin generation, most likely because binding results in prorenin activation.
Batenburg
Wendy W
WW
Erasmus MC, Rotterdam, The Netherlands.
Krop
Manne
M
Garrelds
Ingrid M
IM
de Vries
René
R
de Bruin
René J A
RJ
Burcklé
Celine A
CA
Müller
Dominik N
DN
Bader
Michael
M
Nguyen
Geneviève
G
Danser
A H Jan
AH
D000808:Angiotensinogen / Q000378:metabolism / Q000494:pharmacology; D000809:Angiotensins / Q000096:biosynthesis; D000818:Animals; D030801:Animals, Genetically Modified; D002478:Cells, Cultured; D006801:Humans; D007083:Iliac Artery / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007700:Kinetics; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017527:Receptor, IGF Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012083:Renin / Q000378:metabolism* / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D000093342:Prorenin Receptor
D000809:Angiotensins; D011498:Protein Precursors; D017527:Receptor, IGF Type 2; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D000808:Angiotensinogen; D012083:Renin; D000093342:Prorenin Receptor