FGF21 Prevents Angiotensin II-Induced Hypertension and Vascular Dysfunction by Activation of ACE2/Angiotensin-(1-7) Axis in Mice
FGF21 Prevents Angiotensin II-Induced Hypertension and Vascular Dysfunction by Activation of ACE2/Angiotensin-(1-7) Axis in Mice
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DOI：
10.1016/j.cmet.2018.04.002
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发表时间：
2018-06-05
期刊：
影响因子：
29
通讯作者：
Lin, Zhuofeng
中科院分区：
文献类型：
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作者：
Pan, Xuebo;Shao, Yihui;Lin, Zhuofeng
成纤维细胞生长因子21(FGF21)是一种对糖脂代谢和胰岛素敏感性具有多效性的代谢激素。然而，FGF21在高血压中的作用仍然不清楚。在这里，我们显示FGF21缺乏显著加重血管紧张素II诱导的高血压和血管功能障碍，而这种负面影响被FGF21的补充所逆转。从机制上讲，FGF21作用于脂肪细胞和肾细胞，促进血管紧张素转换酶2(ACE2)的诱导，进而将血管紧张素II转化为血管紧张素(1-7)，从而抑制高血压，逆转血管损伤。此外，ACE2缺乏显著地剥夺了FGF21对小鼠的这些有益作用，包括缓解血管紧张素II相关的高血压和血管损伤。此外，药物抑制血管紧张素-(1-7)可减弱FGF21对血管紧张素II诱导的血管功能障碍的保护作用，但不会减弱对高血压的保护作用。因此，FGF21通过微调肝脏、脂肪组织、肾脏和血管之间的多器官串扰，激活ACE2/血管紧张素-(1-7)轴，从而保护血管免受血管紧张素II诱导的高血压和血管损伤。
Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulin sensitivity. However, the role of FGF21 in hypertension remains elusive. Here we show that FGF21 deficiency significantly exacerbates angiotensin II-induced hypertension and vascular dysfunction, whereas such negative effects are reversed by replenishment of FGF21. Mechanistically, FGF21 acts on adipocytes and renal cells to promote induction of angiotensin-converting enzyme2 (ACE2), which in turn converts angiotensin II to angiotensin(1-7), then inhibits hypertension and reverses vascular damage. In addition, ACE2 deficiency strikingly abrogates these beneficial effects of FGF21 in mice, including alleviation of angiotensin II-associated hypertension and vascular damage. Otherwise, pharmaceutical inhibition of angiotensin-(1-7) attenuates the protective effect of FGF21 on angiotensin II-induced vascular dysfunction, but not on hypertension. Thus, FGF21 protects against angiotensin II-induced hypertension and vascular impairment by activation of the ACE2/angiotensin-(1-7) axis via fine-tuning the multi-organ crosstalk between liver, adipose tissue, kidney, and blood vessels.