Pharmacological Npt2a Inhibition Causes Phosphaturia and Reduces Plasma Phosphate in Mice with Normal and Reduced Kidney Function.
Animals
Calcium
/ urine
Disease Models, Animal
Dose-Response Relationship, Drug
Fibroblast Growth Factor-23
Fibroblast Growth Factors
/ blood
Hypophosphatemia, Familial
/ etiology
Male
Mice
Mice, Inbred C57BL
Parathyroid Hormone
/ blood
Phosphates
/ blood
Renal Insufficiency, Chronic
/ metabolism
Sodium-Phosphate Cotransporter Proteins, Type IIa
/ antagonists & inhibitors
Cell & Transport Physiology
calcium
chronic kidney disease
electrolytes
hyperphosphatemia
phosphate uptake
Journal
Journal of the American Society of Nephrology : JASN
ISSN: 1533-3450
Titre abrégé: J Am Soc Nephrol
Pays: United States
ID NLM: 9013836
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
received:
20
12
2018
accepted:
14
07
2019
pubmed:
15
8
2019
medline:
2
6
2020
entrez:
15
8
2019
Statut:
ppublish
Résumé
The kidneys play an important role in phosphate homeostasis. Patients with CKD develop hyperphosphatemia in the later stages of the disease. Currently, treatment options are limited to dietary phosphate restriction and oral phosphate binders. The sodium-phosphate cotransporter Npt2a, which mediates a large proportion of phosphate reabsorption in the kidney, might be a good therapeutic target for new medications for hyperphosphatemia. The authors assessed the effects of the first orally bioavailable Npt2a inhibitor (Npt2a-I) PF-06869206 in normal mice and mice that had undergone subtotal nephrectomy (5/6 Nx), a mouse model of CKD. Dose-response relationships of sodium, chloride, potassium, phosphate, and calcium excretion were assessed in response to the Npt2a inhibitor in both groups of mice. Expression and localization of Npt2a/c and levels of plasma phosphate, calcium, parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) were studied up to 24-hours after Npt2a-I treatment. In normal mice, Npt2a inhibition caused a dose-dependent increase in urinary phosphate (ED Npt2a inhibition causes a dose-dependent increase in phosphate, sodium and chloride excretion associated with reductions in plasma phosphate and PTH levels in normal mice and in a CKD mouse model.
Sections du résumé
BACKGROUND
The kidneys play an important role in phosphate homeostasis. Patients with CKD develop hyperphosphatemia in the later stages of the disease. Currently, treatment options are limited to dietary phosphate restriction and oral phosphate binders. The sodium-phosphate cotransporter Npt2a, which mediates a large proportion of phosphate reabsorption in the kidney, might be a good therapeutic target for new medications for hyperphosphatemia.
METHODS
The authors assessed the effects of the first orally bioavailable Npt2a inhibitor (Npt2a-I) PF-06869206 in normal mice and mice that had undergone subtotal nephrectomy (5/6 Nx), a mouse model of CKD. Dose-response relationships of sodium, chloride, potassium, phosphate, and calcium excretion were assessed in response to the Npt2a inhibitor in both groups of mice. Expression and localization of Npt2a/c and levels of plasma phosphate, calcium, parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) were studied up to 24-hours after Npt2a-I treatment.
RESULTS
In normal mice, Npt2a inhibition caused a dose-dependent increase in urinary phosphate (ED
CONCLUSIONS
Npt2a inhibition causes a dose-dependent increase in phosphate, sodium and chloride excretion associated with reductions in plasma phosphate and PTH levels in normal mice and in a CKD mouse model.
Identifiants
pubmed: 31409727
pii: ASN.2018121250
doi: 10.1681/ASN.2018121250
pmc: PMC6830793
doi:
Substances chimiques
Fgf23 protein, mouse
0
Parathyroid Hormone
0
Phosphates
0
Slc34a1 protein, mouse
0
Sodium-Phosphate Cotransporter Proteins, Type IIa
0
Fibroblast Growth Factors
62031-54-3
Fibroblast Growth Factor-23
7Q7P4S7RRE
Calcium
SY7Q814VUP
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
2128-2139Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK110621
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 by the American Society of Nephrology.
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