Increased fibroblast growth factor-21 in chronic kidney disease is a trade-off between survival benefit and blood pressure dysregulation

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.

Scalable fabrication of renal spheroids and nephron-like tubules by bioprinting and controlled self-assembly of epithelial cells

“…We found that 379 genes (78.8%) were upregulated, while only 102 genes (21.2%) were downregulated in bioprinted and self-assembled iREC tubules. GO-term analysis revealed enrichment in cellular processes, such as response to fibroblast growth factor and organic anion transport, both of which are relevant to the formation of tubular kidney structures in vivo (figure 4(b)) [45][46][47]. Among the robustly up-regulated transcripts (log 2 FC > 1), we found 34 to be enriched in the kidneys with a median expression level two times higher than in other tissues (figure 4(c)).…”

The Multiple Roles of Fibroblast Growth Factor in Diabetic Nephropathy

“…Although the increase of FGF21 increases the cardiovascular risk, it is necessary for the survival of CKD mice. 54 , 83 , 84 Furthermore, the analysis results of clinical samples of diabetic patients with chronic kidney disease showed that when glomerular filtration rate was high, serum FGF21 levels increased with proteinuria but were relatively low in the kidneys. The elevated levels of FGF21 in patients with DN may be due to the increased secretion of the body for protection purposes under the stimulation of stress responses such as inflammation and oxidative stress.…”

Roles of fibroblast growth factor 21 in the control of depression‐like behaviours after social defeat stress in male rodents

“…The same brains were used in a previous study showing single immunocytochemical detection of c-Fos protein. 24…”

“…AAV8 vectors expressing mouse FGF21 or humanised Renilla reniformis green fluorescent protein (hrGFP) under the control of the CAG promoter (chicken β-actin promoter with the cytomegalovirus immediateearly enhancer) were prepared as described previously. 24,27 In brief, 293 cells were transfected simultaneously with adenovirus helper plasmid, AAV type 8 helper plasmid, and the hrGFP or FGF21 plasmid by calcium phosphate transfection and were maintained for 3 days.…”

“…injection of FGF21 activated cells in the nucleus tractus solitarius in rats. 24 Using these brains, we first determined whether central administration of FGF21 activated catecholaminergic neurones in the nucleus tractus solitarius by examining the expression of c-Fos protein in tyrosine hydroxylase-positive neurones in the medulla oblongata. We next determined whether tyrosine hydroxylase-positive neurones in the nucleus tractus solitarius expressed β-Klotho mRNA using double in situ hybridisation.…”