Aliskiren restores renal AQP2 expression during unilateral ureteral obstruction by inhibiting the inflammasome
Aliskiren restores renal AQP2 expression during unilateral ureteral obstruction by inhibiting the inflammasome
复制标题
阿利吉仑通过抑制炎症小体恢复单侧输尿管梗阻期间肾脏 AQP2 的表达
DOI：
10.1152/ajprenal.00649.2014
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发表时间：
2015-04-15
影响因子：
4.2
通讯作者：
Li, Chunling
中科院分区：
文献类型：
--
作者：
Wang, Weidong;Luo, Renfei;Li, Chunling
输尿管梗阻与肾水通道蛋白（AQP）表达减少、尿浓缩缺陷和炎症反应增强有关，其中肾素-血管紧张素系统（RAS）可能起重要作用。我们评估了在单侧输尿管梗阻（UUO）模型中，直接的肾素抑制剂阿利吉仑阻断RAS是否会阻止肾脏AQP蛋白表达的降低，以及可能涉及的潜在机制。在C57 BL/6小鼠中进行UUO 3天（3UUO）和7天（7 UUO），注射或不注射阿利吉仑。在3UUO和7 UUO小鼠中，阿利吉仑消除了AQP 2蛋白表达的降低，但不能消除AQP 1、AQP 3和AQP 4。肾AQP 2和血管加压素2型受体的mRNA水平降低7 UUO小鼠梗阻肾，这是预防阿利吉仑治疗。阿利吉仑治疗还与UUO小鼠阻塞肾脏中炎症反应的减少有关。阿利吉仑显著降低了几种促炎因子的mRNA水平，如转化生长因子-β和肿瘤坏死因子-α，见于UUO小鼠阻塞的肾脏。有趣的是，在7 UUO小鼠阻塞的肾脏中，NOD样受体家族、含pyrin结构域3（NLRP 3）炎性小体组分、含半胱天冬酶募集结构域的凋亡相关斑点样蛋白、半胱天冬酶-1和IL-1 β的mRNA和蛋白水平显著升高，而阿利吉仑显著抑制了这一点。在原代培养的内髓集合管细胞中，IL-1 β显著降低AQP 2表达。总之，RAS阻断与直接的肾素抑制剂阿利吉仑增加水通道AQP 2的表达在UUO小鼠梗阻的肾脏，至少部分通过防止与输尿管梗阻相关的NLRP 3炎性体激活。
Ureteral obstruction is associated with reduced expression of renal aquaporins (AQPs), urinary concentrating defects, and an enhanced inflammatory response, in which the renin-angiotensin system (RAS) may play an important role. We evaluated whether RAS blockade by a direct renin inhibitor, aliskiren, would prevent the decreased renal protein expression of AQPs in a unilateral ureteral obstruction (UUO) model and what potential mechanisms may be involved. UUO was performed for 3 days (3UUO) and 7 days (7UUO) in C57BL/6 mice with or without aliskiren injection. In 3UUO and 7UUO mice, aliskiren abolished the reduction of AQP2 protein expression but not AQP1, AQP3, and AQP4. mRNA levels of renal AQP2 and vasopressin type 2 receptor were decreased in obstructed kidneys of 7UUO mice, which were prevented by aliskiren treatment. Aliskiren treatment was also associated with a reduced inflammatory response in obstructed kidneys of UUO mice. Aliskiren significantly decreased mRNA levels of several proinflammatory factors, such as transforming growth factor-beta and tumor necrosis factor-alpha, seen in obstructed kidneys of UUO mice. Interestingly, mRNA and protein levels of the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome components apoptosis-associated speck-like protein containing a caspase recruitment domain, caspase-1, and IL-1 beta were dramatically increased in obstructed kidneys of 7UUO mice, which were significantly suppressed by aliskiren. In primary cultured inner medullary collecting duct cells, IL-1 beta significantly decreased AQP2 expression. In conclusions, RAS blockade with the direct renin inhibitor aliskiren increased water channel AQP2 expression in obstructed kidneys of UUO mice, at least partially by preventing NLRP3 inflammasome activation in association with ureteral obstruction.