Aliskiren accumulation in the kidney: no major role for binding to renin or prorenin
Aliskiren accumulation in the kidney: no major role for binding to renin or prorenin
复制标题
DOI：
10.1097/hjh.0b013e32835e226b
复制
发表时间：
2013-04-01
影响因子：
4.9
通讯作者：
Wenzel, Ulrich Otto
中科院分区：
文献类型：
--
作者：
Lange, Sascha;Fraune, Christoph;Wenzel, Ulrich Otto
背景和目的：基于其血浆半衰期，直接肾素抑制剂阿利吉仑的降压作用在停药后持续时间比预期的要长得多。这可能归因于最近在大鼠和小鼠身上显示的药物在肾脏中的积累。由于阿利吉伦与肾素结合，我们在本研究中检验了这种蓄积是否依赖于肾脏的肾素含量。方法：为此，我们测量了野生型、AT1a受体(-/-)和Ren1c(-/-)小鼠肾脏中阿利吉伦的浓度。AT1a受体(-/-)小鼠由于缺乏血管紧张素II介导的负反馈而过度表达肾素，而Ren1c(-/-)小鼠肾脏肾素表达不足。然而，肾脏蓄积既不受肾脏中肾素过度表达的影响，也不受肾脏中肾素缺乏的影响。最近研究表明，阿利吉仑的作用可以被一个手柄区域的多肽所阻断，该多肽可以抑制(Pro)肾素受体结合的前肾素的非蛋白水解性激活。为了研究这种假定的肾素受体阻滞剂是否影响阿利吉伦的肾积聚，我们在阿利吉伦的基础上加用该阻滞剂。结论：这些数据证实了阿利吉伦在小鼠肾脏中的蓄积，并表明肾素和(PRO)肾素受体结合的前肾素都不是这一过程中的主要参与者。
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.