Department of Cardiology, Nanjing University Medical School Affiliated Nanjing, Drum Tower Hospital, Nanjing, China.
Department of Cardiology, Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Eur J Pharmacol. 2020 Sep 5;882:173228. doi: 10.1016/j.ejphar.2020.173228. Epub 2020 Jun 2.
The current study was designed to examine the protection of RAGE-specific inhibitor FPS-ZM1 against renal injury in spontaneously hypertensive rats (SHR) and investigate the underlying mechanism. The adult male SHR were treated with FPS-ZM1 via oral gavages for 12 weeks, and age-matched male Wistar-Kyoto rats (WKY) were used as control. Treatment of SHR with FPS-ZM1 slightly reduced blood pressure, and significantly improved baroreflex sensitivity in SHR. Treatment of SHR with FPS-ZM1 improved renal function, evidenced by increased glomerular filtration rate and renal blood flow, and reduced plasma creatinine, blood urea nitrogen and urine albumin excretion rate. Histology results revealed that treatment of SHR with FPS-ZM1 alleviated renal injury and reduced tubulointerstitial fibrosis. Treatment of SHR with FPS-ZM1 suppressed activation of NF-κB and reduced expression of pro-inflammatory cytokines including Tnf, Il6, and Il1b. Treatment of SHR with FPS-ZM1 abated oxidative stress and downregulated mRNA levels of components of NADPH oxidase (Nox) including Cyba, Nox1, Nox2, Nox4 and Ncf1 in kidneys. In addition, treatment of SHR with FPS-ZM1 reduced renal AngII levels, downregulated mRNA expression of Ace and upregulated expression of Agtr2. In conclusion, treatment with FPS-ZM1 alleviated hypertension-related renal dysfunction, possibly by suppressing NF-κB-mediated inflammation, abating Nox-mediated oxidative stress, and improving local renal renin-angiotensin system (RAS).
本研究旨在探讨 RAGE 特异性抑制剂 FPS-ZM1 对自发性高血压大鼠（SHR）肾损伤的保护作用，并探讨其潜在机制。成年雄性 SHR 经口服灌胃给予 FPS-ZM1 治疗 12 周，同时设年龄匹配的雄性 Wistar-Kyoto 大鼠（WKY）为对照组。FPS-ZM1 治疗 SHR 可轻度降低血压，并显著提高 SHR 的压力感受性反射敏感性。FPS-ZM1 治疗 SHR 可改善肾功能，表现为肾小球滤过率和肾血流量增加，血浆肌酐、血尿素氮和尿白蛋白排泄率降低。组织学结果显示，FPS-ZM1 治疗可减轻 SHR 的肾损伤和小管间质纤维化。FPS-ZM1 治疗可抑制 NF-κB 活化，减少 TNF、IL6 和 IL1b 等促炎细胞因子的表达。FPS-ZM1 治疗可减轻氧化应激，下调肾脏 NADPH 氧化酶（Nox）各组分（Cyba、Nox1、Nox2、Nox4 和 Ncf1）的 mRNA 水平。此外，FPS-ZM1 治疗还可降低 SHR 的肾 AngII 水平，下调 Ace 的 mRNA 表达，上调 Agtr2 的表达。综上，FPS-ZM1 治疗可缓解高血压相关的肾功能障碍，可能是通过抑制 NF-κB 介导的炎症、减轻 Nox 介导的氧化应激以及改善局部肾素-血管紧张素系统（RAS）实现的。
