Ling Yeong Hann, Krishnan Shalini M, Chan Christopher T, Diep Henry, Ferens Dorota, Chin-Dusting Jaye, Kemp-Harper Barbara K, Samuel Chrishan S, Hewitson Timothy D, Latz Eicke, Mansell Ashley, Sobey Christopher G, Drummond Grant R
Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Australia.
Department of Nephrology, Royal Melbourne Hospital, Parkville, Australia.
Pharmacol Res. 2017 Feb;116:77-86. doi: 10.1016/j.phrs.2016.12.015. Epub 2016 Dec 13.
To determine whether a clinically-utilised IL-1 receptor antagonist, anakinra, reduces renal inflammation, structural damage and blood pressure (BP) in mice with established hypertension.
Hypertension was induced in male mice by uninephrectomy, deoxycorticosterone acetate (2.4mg/d,s.c.) and replacement of drinking water with saline (1K/DOCA/salt). Control mice received uninephrectomy, a placebo pellet and normal drinking water. 10days post-surgery, mice commenced treatment with anakinra (75mg/kg/d, i.p.) or vehicle (0.9% saline, i.p.) for 11days. Systolic BP was measured by tail cuff while qPCR, immunohistochemistry and flow cytometry were used to measure inflammatory markers, collagen and immune cell infiltration in the kidneys.
By 10days post-surgery, 1K/DOCA/salt-treated mice displayed elevated systolic BP (148.3±2.4mmHg) compared to control mice (121.7±2.7mmHg; n=18, P<0.0001). The intervention with anakinra reduced BP in 1K/DOCA/salt-treated mice by ∼20mmHg (n=16, P<0.05), but had no effect in controls. In 1K/DOCA/salt-treated mice, anakinra modestly reduced (∼30%) renal expression of some (CCL5, CCL2; n=7-8; P<0.05) but not all (ICAM-1, IL-6) inflammatory markers, and had no effect on immune cell infiltration (n=7-8, P>0.05). Anakinra reduced renal collagen content (n=6, P<0.01) but paradoxically appeared to exacerbate the renal and glomerular hypertrophy (n=8-9, P<0.001) that accompanied 1K/DOCA/salt-induced hypertension.
Despite its anti-hypertensive and renal anti-fibrotic actions, anakinra had minimal effects on inflammation and leukocyte infiltration in mice with 1K/DOCA/salt-induced hypertension. Future studies will assess whether the anti-hypertensive actions of anakinra are mediated by protective actions in other BP-regulating or salt-handling organs such as the arteries, skin and brain.
确定临床应用的白细胞介素-1受体拮抗剂阿那白滞素是否能减轻已患高血压小鼠的肾脏炎症、结构损伤和血压。
通过单侧肾切除、皮下注射醋酸脱氧皮质酮（2.4mg/d）并用盐水替代饮用水（1K/DOCA/盐）诱导雄性小鼠患高血压。对照小鼠接受单侧肾切除、安慰剂丸和正常饮用水。术后10天，小鼠开始用阿那白滞素（75mg/kg/d，腹腔注射）或溶媒（0.9%盐水，腹腔注射）治疗11天。通过尾袖法测量收缩压，同时采用定量聚合酶链反应、免疫组织化学和流式细胞术测量肾脏中的炎症标志物、胶原蛋白和免疫细胞浸润情况。
术后10天，1K/DOCA/盐处理的小鼠收缩压（148.3±2.4mmHg）高于对照小鼠（121.7±2.7mmHg；n=18，P<0.0001）。阿那白滞素干预使1K/DOCA/盐处理的小鼠血压降低约20mmHg（n=16，P<0.05），但对对照小鼠无影响。在1K/DOCA/盐处理的小鼠中，阿那白滞素适度降低了部分（趋化因子配体5、趋化因子配体2；n=7-8；P<0.05）而非全部（细胞间黏附分子-1、白细胞介素-6）炎症标志物的肾脏表达，且对免疫细胞浸润无影响（n=7-8，P>0.05）。阿那白滞素降低了肾脏胶原蛋白含量（n=6，P<0.01），但矛盾的是，似乎加剧了伴随1K/DOCA/盐诱导高血压出现的肾脏和肾小球肥大（n=8-9，P<0.001）。
尽管阿那白滞素有抗高血压和肾脏抗纤维化作用，但对1K/DOCA/盐诱导高血压小鼠的炎症和白细胞浸润影响极小。未来研究将评估阿那白滞素的抗高血压作用是否由其在其他血压调节或盐处理器官（如动脉、皮肤和大脑）中的保护作用介导。
