Augmenting Renal Lymphatic Density Prevents Angiotensin II-Induced Hypertension in Male and Female Mice
Augmenting Renal Lymphatic Density Prevents Angiotensin II-Induced Hypertension in Male and Female Mice
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DOI：
10.1093/ajh/hpz139
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发表时间：
2020-01-01
影响因子：
3.2
通讯作者：
Mitchell, Brett M.
中科院分区：
文献类型：
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作者：
Balasubbramanian, Dakshnapriya;Gelston, Catalina A. Lopez;Mitchell, Brett M.
肾脏炎症和免疫细胞浸润是几种高血压的特征。我们的实验室先前已经证明，肾脏炎症相关的淋巴管生成发生在盐敏感性和一氧化氮抑制诱导的高血压。此外，增加肾淋巴管密度防止这两种形式的高血压的发展。在这里，我们研究了血管紧张素II诱导的高血压对雄性和雌性小鼠肾淋巴管密度的影响。方法野生型和基因工程雄性和雌性小鼠输注血管紧张素II 2或3周。与载体对照相比，血管紧张素II输注的雄性和雌性小鼠具有与这些小鼠肾脏中的促炎免疫细胞相关的显著增加的肾淋巴管密度。用血管紧张素II直接治疗淋巴管内皮细胞没有效果，因为它们缺乏血管紧张素II受体;然而，血管紧张素II治疗脾细胞和腹腔巨噬细胞诱导体外淋巴管生成生长因子VEGF-C的分泌。利用我们的可诱导肾淋巴管生成的遗传小鼠模型，我们证明了在血管紧张素II输注之前大大增加肾淋巴管密度可以防止雄性和雌性小鼠高血压的发展，这与肾CD 11 c +F4/80单核细胞的减少有关。并代表了治疗高血压的新途径。
BACKGROUNDRenal inflammation and immune cell infiltration are characteristic of several forms of hypertension. Our laboratory has previously demonstrated that renal-inflammation-associated lymphangiogenesis occurs in salt-sensitive and nitric-oxide-inhibition-induced hypertension. Moreover, enhancing renal lymphatic density prevented the development of these two forms of hypertension. Here, we investigated the effects of angiotensin II-induced hypertension on renal lymphatic vessel density in male and female mice.METHODSWild-type and genetically engineered male and female mice were infused with angiotensin II for 2 or 3 weeks. Isolated splenocytes and peritoneal macrophages from mice, and commercially available mouse lymphatic endothelial cells were used for in vitro studies.RESULTSCompared to vehicle controls, angiotensin II-infused male and female mice had significantly increased renal lymphatic vessel density in association with pro-inflammatory immune cells in the kidneys of these mice. Direct treatment of lymphatic endothelial cells with angiotensin II had no effect as they lack angiotensin II receptors; however, angiotensin II treatment of splenocytes and peritoneal macrophages induced secretion of the lymphangiogenic growth factor VEGF-C in vitro. Utilizing our genetic mouse model of inducible renal lymphangiogenesis, we demonstrated that greatly augmenting renal lymphatic density prior to angiotensin II infusion prevented the development of hypertension in male and female mice and this was associated with a reduction in renal CD11c+F4/80 monocytes.CONCLUSIONRenal lymphatics play a significant role in renal immune cell trafficking and blood pressure regulation, and represent a novel avenue of therapy for hypertension.