FGF21 Prevents Angiotensin II-Induced Hypertension and Vascular Dysfunction by Activation of ACE2/Angiotensin-(1–7) Axis in Mice

• Published in: Cell metabolism 2018-06, Vol.27 (6), p.1323-1337.e5
• Main Authors: Pan, Xuebo, Shao, Yihui, Wu, Fan, Wang, Yuan, Xiong, Rongrong, Zheng, Jujia, Tian, Haishan, Wang, Baile, Wang, Yanfang, Zhang, Yi, Han, Zongsheng, Qu, Aijuan, Xu, Haixia, Lu, Aihua, Yang, Tianxin, Li, Xiaokun, Xu, Aimin, Du, Jie, Lin, Zhuofeng
• Format: Article
• Language: English
• Subjects: ACE2; angiotensin II; angiotensin-(1–7); FGF21; hypertension
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2018.04.002

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 enzyme 2 (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. [Display omitted] •FGF21 is significantly increased in angiotensin II-induced hypertensive mice•FGF21 induces production of ACE2 and Ang-(1–7) in adipocytes and renal cells•ACE2 is obligatory for FGF21 reversing Ang II-induced hypertension•The FGF21-ACE2 axis couples multi-organs to reverse Ang II-induced hypertension Pan et al. show that the metabolic hormone fibroblast growth factor 21 (FGF21) plays an important role in blood pressure regulation by counteracting angiotensin II-induced hypertension and vessel injury. Mechanistically, FGF21 acts on adipocytes and renal cells to promote induction of ACE2, a carboxypeptidase that metabolizes angiotensin II to angiotensin-(1–7).