The HIF-PHI BAY 85-3934 (Molidustat) Improves Anemia and Is Associated With Reduced Levels of Circulating FGF23 in a CKD Mouse Model.
ANEMIA
CKD
FGF23
HIF-PHI
IRON
MOLIDUSTAT
Journal
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
ISSN: 1523-4681
Titre abrégé: J Bone Miner Res
Pays: United States
ID NLM: 8610640
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
revised:
01
02
2021
received:
23
10
2020
accepted:
10
02
2021
pubmed:
17
2
2021
medline:
10
8
2021
entrez:
16
2
2021
Statut:
ppublish
Résumé
Fibroblast growth factor-23 (FGF23) is a critical factor in chronic kidney disease (CKD), with elevated levels causing alterations in mineral metabolism and increased odds for mortality. Patients with CKD develop anemia as the kidneys progressively lose the ability to produce erythropoietin (EPO). Anemia is a potent driver of FGF23 secretion; therefore, a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) currently in clinical trials to elevate endogenous EPO to resolve anemia was tested for effects on iron utilization and FGF23-related parameters in a CKD mouse model. Mice were fed either a casein control diet or an adenine-containing diet to induce CKD. The CKD mice had markedly elevated iFGF23 and blood urea nitrogen (BUN), hyperphosphatemia, and anemia. Cohorts of mice were then treated with a patient-equivalent dose of BAY 85-3934 (BAY; Molidustat), which elevated EPO and completely resolved aberrant complete blood counts (CBCs) in the CKD mice. iFGF23 was elevated in vehicle-treated CKD mice (120-fold), whereas circulating iFGF23 was significantly attenuated (>60%) in the BAY-treated CKD mice. The BAY-treated mice with CKD also had reduced BUN, but there was no effect on renal vitamin D metabolic enzyme expression. Consistent with increased EPO, bone marrow Erfe, Transferrin receptor (Tfrc), and EpoR mRNAs were increased in BAY-treated CKD mice, and in vitro hypoxic marrow cultures increased FGF23 with direct EPO treatment. Liver Bmp-6 and hepcidin expression were downregulated in all BAY-treated groups. Femur trabecular parameters and cortical porosity were not worsened with BAY administration. In vitro, differentiated osteocyte-like cells exposed to an iron chelator to simulate iron depletion/hypoxia increased FGF23; repletion with holo-transferrin completely suppressed FGF23 and normalized Tfrc1. Collectively, these results support that resolving anemia using a HIF-PHI during CKD was associated with lower BUN and reduced FGF23, potentially through direct restoration of iron utilization, thus providing modifiable outcomes beyond improving anemia for this patient population. © 2021 American Society for Bone and Mineral Research (ASBMR).
Identifiants
pubmed: 33592127
doi: 10.1002/jbmr.4272
pmc: PMC8255270
mid: NIHMS1692280
doi:
Substances chimiques
FGF23 protein, human
0
Fgf23 protein, mouse
0
Pyrazoles
0
Triazoles
0
Fibroblast Growth Factors
62031-54-3
Fibroblast Growth Factor-23
7Q7P4S7RRE
molidustat
9JH486CZ13
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1117-1130Subventions
Organisme : NHLBI NIH HHS
ID : T32 HL007910
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL145528
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK112958
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35 HL139599
Pays : United States
Organisme : NIDDK NIH HHS
ID : U54 DK106846
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR074473
Pays : United States
Organisme : NIAMS NIH HHS
ID : R21 AR059278
Pays : United States
Organisme : NIDDK NIH HHS
ID : F31 DK122679
Pays : United States
Informations de copyright
© 2021 American Society for Bone and Mineral Research (ASBMR).
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