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Circulating levels of fibroblast growth factor 21 (FGF21) are known to be associated with hypertension in humans, and administration of FGF21 ameliorates high blood pressure in a rat model of hypertension. However, the mechanisms underlying this association are unclear. Now, new research suggests that FGF21 activates the angiotensin-converting enzyme 2 (ACE2)–angiotensin (1–7) axis, which protects against angiotensin II-induced hypertension.

Confirming the prior observations in humans, Zhuofeng Lin and colleagues demonstrated that mice treated with angiotensin II had increased Fgf21 expression in the liver and raised serum levels of FGF21. Next, the researchers examined FGF21-knockout mice. Basal blood pressure and heart rate were similar in wild-type and knockout mice; however, angiotensin II-induced hypertension was found to be worse in the knockout mice compared with the wild-type mice, with significantly increased average systolic and diastolic pressures.

ACE2, which metabolizes angiotensin II to angiotensin (1–7), has a role in maintaining blood pressure homeostasis by negatively modulating the renin–angiotensin system. “In this project, we provide both in vivo and in vitro experimental data to clarify how ACE2 mediates the protective effect of FGF21 against angiotensin II-induced hypertension,” explains Lin. “It is the first time the relationship between these two important proteins has been identified.” In a series of experiments, Lin and colleagues showed that FGF21 induces the activity of ACE2 derived from adipocytes and renal cells, which protected against hypertension caused by angiotensin II, and also reversed vascular damage.

ACE2 mediates the protective effect of FGF21 against angiotensin II-induced hypertension

The authors note that their findings need to be confirmed in large non-human animals and in clinical studies. “The molecular mechanisms of FGF21 protecting against salt-induced hypertension need further investigation,” adds Lin. The researchers are now planning to focus on these questions. “Our study may raise the possibility that FGF21 or its agonists are more effective for the treatment of hypertension than for diabetes,” concludes Lin.