New Renin Inhibitor VTP-27999 Alters Renin Immunoreactivity and Does Not Unfold Prorenin

Abstract
Renin inhibitors like aliskiren not only block renin but also bind prorenin, thereby inducing a conformational change (like the change induced by acid) allowing its recognition in a renin-specific assay. Consequently, aliskiren can be used to measure prorenin. VTP-27999 is a new renin inhibitor with an aliskiren-like IC50 and t1/2, and a much higher bioavailability. This study addressed (pro)renin changes during treatment of volunteers with VTP-27999 or aliskiren. Both drugs increased renin immunoreactivity. Treatment of plasma samples from aliskiren-treated subjects with excess aliskiren yielded higher renin immunoreactivity levels, confirming the presence of prorenin. Unexpectedly, this approach did not work in VTP-27999–treated subjects, although an assay detecting the prosegment revealed that their blood still contained prorenin. Subsequent in vitro analysis showed that VTP-27999 increased renin immunoreactivity for a given amount of renin by ≥30% but did not unfold prorenin. Yet, it did bind to acid-activated, intact prorenin and then again increased immunoreactivity in a renin assay. However, no such increase in immunoreactivity was seen when measuring acid-activated prorenin bound to VTP-27999 with a prosegment-directed assay. The VTP-27999–induced rises in renin immunoreactivity could be competitively prevented by aliskiren, and antibody displacement studies revealed a higher affinity of the active site-directed antibodies in the presence of VTP-27999. In conclusion, VTP-27999 increases renin immunoreactivity in renin immunoassays because it affects the affinity of the active site-directed antibody. Combined with its lack of effect on prorenin, these data show that VTP-27999 differs from aliskiren. The clinical relevance of these results needs to be established.
- Received December 27, 2012.
- Revision received February 7, 2013.
- Accepted February 10, 2013.
- © 2013 American Heart Association, Inc.
Current Issue
Article Tools
- New Renin Inhibitor VTP-27999 Alters Renin Immunoreactivity and Does Not Unfold ProreninManne Krop, Xifeng Lu, Koen Verdonk, Maarten A.D.H. Schalekamp, Jeanette M.G. van Gool, Brian M. McKeever, Richard Gregg and A.H. Jan DanserHypertension. 2013;HYPERTENSIONAHA.111.00967, originally published March 4, 2013https://doi.org/10.1161/HYPERTENSIONAHA.111.00967
Citation Manager Formats
Share this Article
- New Renin Inhibitor VTP-27999 Alters Renin Immunoreactivity and Does Not Unfold ProreninManne Krop, Xifeng Lu, Koen Verdonk, Maarten A.D.H. Schalekamp, Jeanette M.G. van Gool, Brian M. McKeever, Richard Gregg and A.H. Jan DanserHypertension. 2013;HYPERTENSIONAHA.111.00967, originally published March 4, 2013https://doi.org/10.1161/HYPERTENSIONAHA.111.00967