Abstract
Circulating levels of fibroblast growth factor-21 (FGF21) start increasing in patients with chronic kidney disease (CKD) since early stages during the cause of disease progression. FGF21 is a liver-derived hormone that induces responses to stress through acting on hypothalamus to activate the sympathetic nervous system and the hypothalamus-pituitary-adrenal endocrine axis. However, roles that FGF21 plays in pathophysiology of CKD remains elusive. Here we show in mice that FGF21 is required to survive CKD but responsible for blood pressure dysregulation. When introduced with CKD, Fgf21−/− mice died earlier than wild-type mice. Paradoxically, these Fgf21−/− CKD mice escaped several complications observed in wild-type mice, including augmentation of blood pressure elevating response and activation of the sympathetic nervous system during physical activity and increase in serum noradrenalin and corticosterone levels. Supplementation of FGF21 by administration of an FGF21-expressing adeno-associated virus vector recapitulated these complications in wild-type mice and restored the survival period in Fgf21−/− CKD mice. In CKD patients, high serum FGF21 levels are independently associated with decreased baroreceptor sensitivity. Thus, increased FGF21 in CKD can be viewed as a survival response at the sacrifice of blood pressure homeostasis.
Highlights
Circulating levels of fibroblast growth factor-21 (FGF21) start increasing in patients with chronic kidney disease (CKD) since early stages during the cause of disease progression
There was no difference in the amount of dietary phosphate load between wild-type CKD mice and Fgf21−/− CKD mice, because daily urinary phosphate excretion was comparable between them (Fig. 1c)
Because FGF21 functions as a longevity hormone that extends life span when overexpressed in mice[17], the fact that CKD mice and CKD patients have high serum FGF21 levels may appear inconsistent with their high mortality
Summary
Circulating levels of fibroblast growth factor-21 (FGF21) start increasing in patients with chronic kidney disease (CKD) since early stages during the cause of disease progression. FGF21 is a liverderived hormone that induces responses to stress through acting on hypothalamus to activate the sympathetic nervous system and the hypothalamus-pituitary-adrenal endocrine axis. Unlike the other FGFs that function as paracrine/autocrine growth factors, these three FGFs function as hormones that regulate various metabolic processes, including mineral, glucose, fatty acid, and bile acid metabolism[1] These three FGFs are collectively called endocrine FGFs. Second, endocrine FGFs require the Klotho family of type-I transmembrane proteins (either αKlotho or βKlotho) for high-affinity binding to their cognate FGF receptor (FGFR) tyrosine kinases[2,3,4]. Transgenic mice that overexpress FGF21 live longer than wild-type mice[17], which is consistent with an evolutionarily conserved law that increased ability to handle with stress is associated with extended longevity[18]
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