Aliskiren-binding increases the half life of renin and prorenin in rat aortic vascular smooth muscle cells.
OBJECTIVE
Renin inhibition with aliskiren has been reported to cause a greater rise in renin than other types of renin-angiotensin system blockade, thereby potentially leading to angiotensin generation or stimulation of the human (pro)renin receptor (h(P)RR). Here we studied whether this rise in renin is attributable to an aliskiren-induced change in the prorenin conformation, allowing its detection in renin assays, or a change in renin/prorenin clearance. We also investigated whether aliskiren affects (pro)renin binding to its receptors, using rat aortic vascular smooth muscle cells (VSMCs) overexpressing the h(P)RR.


RESULTS
A 48-hour incubation with aliskiren at 4 degrees C converted the prorenin conformation from "closed" to "open," thus allowing its recognition in active site-directed renin assays. VSMCs accumulated (pro)renin through binding to mannose 6-phosphate receptors (M6PRs) and h(P)RRs. Aliskiren did not affect binding at 4 degrees C. At 37 degrees C, aliskiren increased (pro)renin accumulation up to 40-fold, and M6PR blockade prevented this. Aliskiren increased the intracellular half life of prorenin 2 to 3 times.


CONCLUSIONS
Aliskiren allows the detection of prorenin as renin, and decreases renin/prorenin clearance. Both phenomena may contribute to the "renin" surge during aliskiren treatment, but because they depend on aliskiren binding, they will not result in angiotensin generation. Aliskiren does not affect (pro)renin binding to its receptors.
Batenburg
Wendy W
WW
Erasmus MC, 3015 GE Rotterdam, The Netherlands.
de Bruin
René J A
RJ
van Gool
Jeanette M G
JM
Müller
Dominik N
DN
Bader
Michael
M
Nguyen
Geneviève
G
Danser
A H Jan
AH
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000577:Amides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D000959:Antihypertensive Agents / Q000378:metabolism* / Q000494:pharmacology; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D005650:Fumarates / Q000378:metabolism* / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D012083:Renin / Q000378:metabolism*; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism; D000093342:Prorenin Receptor; D000092502:Renin Inhibitors
D000577:Amides; D000959:Antihypertensive Agents; D005650:Fumarates; D017527:Receptor, IGF Type 2; D011956:Receptors, Cell Surface; D012083:Renin; D025262:Vacuolar Proton-Translocating ATPases; D000093342:Prorenin Receptor; D000092502:Renin Inhibitors; C458319:ATP6AP2 protein, human; C446481:aliskiren