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Aliskiren accumulation in the kidney: no major role for binding to renin or prorenin

Lange, Saschaa,*; Fraune, Christopha,*; Alenina, Nataliab; Bader, Michaelb; Danser, A.H. Janc; Frenay, Anne-Roosd; van Goor, Harryd; Stahl, Rolfa; Nguyen, Genevievee; Schwedhelm, Edzardf; Wenzel, Ulrich Ottoa

Journal of Hypertension:
doi: 10.1097/HJH.0b013e32835e226b
ORIGINAL PAPERS: Renin-angiotensin system
Abstract

Background and objective: The antihypertensive effects of the direct renin inhibitor aliskiren last substantially longer after treatment withdrawal than expected based upon its plasma half-life. This may be attributable to drug accumulation in the kidney as recently shown in rats and mice. Since aliskiren binds to renin we examined in the present study whether this accumulation depends on the renin content of the kidney.

Methods: For this we measured the aliskiren concentration in the kidney of wild-type as well as AT1a receptor−/− and Ren1c−/− mice. AT1a receptor−/− mice overexpress renin due to the lack of angiotensin II-mediated negative feedback, whereas Ren1c−/− mice lack renal renin expression.

Results: Accumulation of aliskiren was found in the kidney of wild-type mice. However, renal accumulation was neither influenced by the overexpression nor by the absence of renin in the kidney. It was recently shown that the effects of aliskiren can be blocked by a handle region peptide, which inhibits the nonproteolytic activation of prorenin bound to the (pro)renin receptor. To investigate whether this putative (pro)renin receptor blocker influences renal aliskiren accumulation, we administered the blocker in addition to aliskiren. No influence on renal aliskiren accumulation was observed.

Conclusion: These data confirm accumulation of aliskiren in the murine kidney and demonstrate that neither renin nor (pro)renin receptor-bound prorenin are major players in this process.

Author Information

aDivision of Nephrology, Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg

bMDC Berlin, Germany

cDivision of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam

dDepartment of Pathology and Medical Biology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands

eCollege de France, Paris, France

fDepartment of Clinical Pharmacology, University Hospital Hamburg-Eppendorf, Hamburg, Germany

*Sascha Lange and Christoph Fraune contributed equally to this paper and are both first authors.

Correspondence to Ulrich Wenzel, Division of Nephrology, Department of Medicine, Universitätsklinikum Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. E-mail: wenzel@uke.de

Abbreviations: ACE, angiotensin-converting enzyme; Ang, angiotensin; ARB, angiotensin receptor blocker; RAS, renin–angiotensin system; AT1a receptor, angiotensin II type 1 receptor; (P)RR, (pro)renin receptor

Received 6 September, 2012

Revised 5 December, 2012

Accepted 19 December, 2012

© 2013 Lippincott Williams & Wilkins, Inc.