A Comprehensive Analysis of Ontogeny of Renal Drug Transporters: mRNA Analyses, Quantitative Proteomics, and Localization.
Adolescent
Adult
Age Factors
Aged
Child
Child, Preschool
Chromatography, Liquid
Female
Humans
Infant
Infant, Newborn
Kidney Cortex
/ metabolism
Male
Membrane Transport Proteins
/ metabolism
Middle Aged
Pregnane X Receptor
/ metabolism
Proteomics
/ methods
RNA, Messenger
/ biosynthesis
Real-Time Polymerase Chain Reaction
Tandem Mass Spectrometry
Young Adult
Journal
Clinical pharmacology and therapeutics
ISSN: 1532-6535
Titre abrégé: Clin Pharmacol Ther
Pays: United States
ID NLM: 0372741
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
received:
09
01
2019
accepted:
23
04
2019
pubmed:
28
5
2019
medline:
2
6
2020
entrez:
26
5
2019
Statut:
ppublish
Résumé
Human renal membrane transporters play key roles in the disposition of renally cleared drugs and endogenous substrates, but their ontogeny is largely unknown. Using 184 human postmortem frozen renal cortical tissues (preterm newborns to adults) and a subset of 62 tissue samples, we measured the mRNA levels of 11 renal transporters and the transcription factor pregnane X receptor (PXR) with quantitative real-time polymerase chain reaction, and protein abundance of nine transporters using liquid chromatography tandem mass spectrometry selective reaction monitoring, respectively. Expression levels of p-glycoprotein, urate transporter 1, organic anion transporter 1, organic anion transporter 3, and organic cation transporter 2 increased with age. Protein levels of multidrug and toxin extrusion transporter 2-K and breast cancer resistance protein showed no difference from newborns to adults, despite age-related changes in mRNA expression. Multidrug and toxin extrusion transporter 1, glucose transporter 2, multidrug resistance-associated protein 2, multidrug resistance-associated protein 4 (MRP4), and PXR expression levels were stable. Using immunohistochemistry, we found that MRP4 localization in pediatric samples was similar to that in adult samples. Collectively, our study revealed that renal drug transporters exhibited different rates and patterns of maturation, suggesting that renal handling of substrates may change with age.
Identifiants
pubmed: 31127606
doi: 10.1002/cpt.1516
pmc: PMC6777991
mid: NIHMS1031847
doi:
Substances chimiques
Membrane Transport Proteins
0
Pregnane X Receptor
0
RNA, Messenger
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1083-1092Subventions
Organisme : FDA HHS
ID : U01 FD005978
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001872
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK103729
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM117163
Pays : United States
Organisme : FDA HHS
ID : U01 FD004979
Pays : United States
Informations de copyright
© 2019 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.
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