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

Abstract

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.

Fibroblast growth factor‐21 protects against fibrosis in hypertensive heart disease

“…Considering the greater extent of FGF21 expression in the liver relative to other tissues, and experimental evidence that the liver has a main role in producing systemic FGF21 , the liver is likely to account for the hypertension‐related increase in FGF21 levels, in agreement with previous reports . Moreover, we found that, unlike Pan et al who previously reported exacerbated hypertensive effects in mice lacking FGF21, our treatment did not cause an overt hypertensive response in Fgf21 ‐deficient mice. The age of the animals, older in our experiment, or the different mouse strain could explain the discrepancy between both experiments.…”

“…As expected, diastolic, systolic and mean arterial pressure (MAP) were significantly increased after 7 days of AngII infusion in WT mice compared with the corresponding untreated CT mice. However, we found no significant differences in diastolic, systolic or MAP pressures between WT and Fgf21 −/− mice after 7 days of AngII infusion, indicating that the alterations observed in Fgf21 −/− mice after a 14‐day AngII‐infusion have not yet occurred with this short‐term treatment; thus, any cardiac effects of the lack of FGF21, if any, would be unrelated to elevated blood pressure.…”

“…Next, to clarify the role of increased FGF21 levels during the pathogenesis of AngII-induced hypertensive heart disease, we evaluated the effects of FGF21 deficiency in mice. In studying the cardiac effects of FGF21 during the development of hypertensive heart disease, it is necessary to avoid the effects of secondary factors reported to be altered in Fgf21 −/− mice after 14 days of AngII treatment, such as remodeling, inflammation and fibrosis of the vasculature, and overt induction of blood pressure [10]. To this end, we chose a shorter, 7-day AngII treatment ( Figure 2).…”

“…Although fibroblasts are responsible for normal collagen turnover, myofibroblasts account for the disproportion-FGF21 protects against cardiac fibrosis 31 a metabolic regulator, are significantly associated with elevated blood pressure in patients with hypertension [8,9]. Moreover, studies in mice have demonstrated that treatment with FGF21 prevents hypertension and vascular dysfunction [10]. FGF21 is mainly produced and released into the blood by the liver [11,12], but extrahepatic tissues, such as white and brown adipose tissues (BATs) also express FGF21 [13][14][15].…”

Counter-regulatory renin–angiotensin system in cardiovascular disease

“…ACE2 might reduce blood pressure levels by generating angiotensin 1-7 from angiotensin II, whereas inhibition of neprilysin increases ANP levels 18 . In addi tion, the endogenous metabolic regulator fibroblast growth factor 21 (FGF21) can promote ACE2 genera tion in adipocytes and renal cells, thereby promoting the cleavage of angiotensin II to form angiotensin 1-7, sug gesting that FGF21 can reduce angiotensin II induced hypertension 19 .…”