Wang Weidong, Luo Renfei, Lin Yu, Wang Feifei, Zheng Peili, Levi Moshe, Yang Tianxin, Li Chunling
Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China;
Division of Renal Diseases and Hypertension, Anschutz Medical Campus, University of Colorado, Aurora, Colorado; and.
Am J Physiol Renal Physiol. 2015 Apr 15;308(8):F910-22. doi: 10.1152/ajprenal.00649.2014. Epub 2015 Feb 18.
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-β and tumor necrosis factor-α, 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-1β were dramatically increased in obstructed kidneys of 7UUO mice, which were significantly suppressed by aliskiren. In primary cultured inner medullary collecting duct cells, IL-1β 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.
输尿管梗阻与肾水通道蛋白（AQP）表达降低、尿浓缩功能缺陷及炎症反应增强有关，其中肾素-血管紧张素系统（RAS）可能起重要作用。我们评估了直接肾素抑制剂阿利吉仑阻断RAS是否能预防单侧输尿管梗阻（UUO）模型中AQP肾蛋白表达的降低以及可能涉及的潜在机制。在有或无阿利吉仑注射的C57BL/6小鼠中进行3天（3UUO）和7天（7UUO）的UUO手术。在3UUO和7UUO小鼠中，阿利吉仑消除了AQP2蛋白表达的降低，但对AQP1、AQP3和AQP4没有影响。7UUO小鼠梗阻肾脏中肾AQP2和血管加压素2型受体的mRNA水平降低，阿利吉仑治疗可预防这种降低。阿利吉仑治疗还与UUO小鼠梗阻肾脏中炎症反应的减轻有关。阿利吉仑显著降低了UUO小鼠梗阻肾脏中几种促炎因子的mRNA水平，如转化生长因子-β和肿瘤坏死因子-α。有趣的是，7UUO小鼠梗阻肾脏中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和白细胞介素-1β等NOD样受体家族含pyrin结构域的3（NLRP3）炎性小体成分的mRNA和蛋白水平显著升高，阿利吉仑可显著抑制这些升高。在原代培养的髓质内集合管细胞中，白细胞介素-1β显著降低AQP2表达。总之，用直接肾素抑制剂阿利吉仑阻断RAS可增加UUO小鼠梗阻肾脏中水通道AQP2的表达，至少部分是通过预防与输尿管梗阻相关的NLRP3炎性小体激活来实现的。
