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.