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

S de Lange, C Fraune, N Alenina, M Bader, Jan Danser, AR Frenay, H van Goor, R Stahl, G Nguyen, E Schwedhelm, UO Wenzel

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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 administere 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.
Original languageUndefined/Unknown
Pages (from-to)713-719
Number of pages7
JournalJournal of Hypertension
Issue number4
Publication statusPublished - 2013

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