Therapeutic effect of prenatal alkalization and PTC124 in Na+/ HCO3- cotransporter 1 p.W516knock-in mice

Y-W Fang; S-S Yang; T. Chau; M. Nakamura; O. Yamazaki; G. Seki; H. Yamada; H-M Hsu; C-J Cheng; S-H Lin

doi:10.1038/gt.2015.7

Back

Therapeutic effect of prenatal alkalization and PTC124 in Na+/ HCO3- cotransporter 1 p.W516knock-in mice

Journal article

Open access

Peer reviewed

Therapeutic effect of prenatal alkalization and PTC124 in Na+/ HCO3- cotransporter 1 p.W516knock-in mice

Y-W Fang, S-S Yang, T. Chau, M. Nakamura, O. Yamazaki, G. Seki, H. Yamada, H-M Hsu, C-J Cheng and S-H Lin

Gene therapy, Vol.22(5), pp.374-381

05/01/2015

DOI: 10.1038/gt.2015.7

PMID: 25716530

Files and links (1)

url

https://doi.org/10.1038/gt.2015.7View

Published (Version of record) Open Access

Abstract

We created Na+/HCO3- cotransporter 1 (NBCe1) p.W516* knock-in mice as a model of isolated proximal renal tubular acidosis showing early lethality associated with severe metabolic acidosis to investigate the therapeutic effects of prenatal alkalization or posttranscriptional control 124 (PTC124). NBCe1(W516*/W516*) mice were treated with non-alkalization (control, n = 12), prenatal alkalization postcoitus (prenatal group, n = 7) and postnatal alkalization from postnatal day 6 (postnatal group, n = 12). Mutationspecific therapy, PTC124 (60 mg kg(-1)) or gentamicin (30 mg kg(-1)), was administered intraperitoneally from postnatal day 6. Blood and urine biochemistry, acid-base analysis, survival rate and renal histology were examined. NBCe1 protein, mRNA abundance and activity ex vivo were assessed after PTC124 and gentamicin treatment. Prenatal group mice had similar initial body weight to wildtype mice and achieved significant weight gain thereafter compared with controls. They had higher serum bicarbonate level (15.5 +/- 1.4 vs 5.5 +/- 0.1 mmol l(-1), P < 0.05) on postnatal day 14 and better renal function, histology and survival rates (60.8 +/- 23.5 vs 41.1 +/- 15.8 days, Po0.05) than the postnatal group. Compared with the control and gentamicin therapies, PTC124 therapy significantly increased NBCe1 protein abundance despite unchanged mRNA transcription. Only PTC124 therapy significantly increased survival rate and partially rescued NBCe1 activity ex vivo. In NBCe1(W516*/W516*) mice, prenatal alkali therapy achieved higher survival rates and ameliorated organ dysfunction. PTC124 therapy for this nonsense mutation was partially effective in increasing NBCe1 expression and activity.

Biochemistry & Molecular Biology

Biotechnology & Applied Microbiology

Genetics & Heredity

Life Sciences & Biomedicine

Medicine, Research & Experimental

Research & Experimental Medicine

Science & Technology

Details

Title: Subtitle: Therapeutic effect of prenatal alkalization and PTC124 in Na+/ HCO3- cotransporter 1 p.W516knock-in mice
Creators: Y-W Fang - National Defense Medical Center
S-S Yang - National Defense Medical Center
T. Chau - National Defense Medical Center
M. Nakamura - Tokyo Medical University
O. Yamazaki - Tokyo Medical University
G. Seki - Tokyo Medical University
H. Yamada - Tokyo Medical University
H-M Hsu - Shin Kong WHS Memorial Hospital
C-J Cheng - National Defense Medical Center
S-H Lin - National Defense Medical Center
Resource Type: Journal article
Publication Details: Gene therapy, Vol.22(5), pp.374-381
DOI: 10.1038/gt.2015.7
PMID: 25716530
NLM abbreviation: Gene Ther
ISSN: 0969-7128
eISSN: 1476-5462
Publisher: Springer Nature
Number of pages: 8
Grant note: SKH-8302-99-DR-07 / Shin Kong Wu Ho-Su Memorial Hospital TSGH-C104-113 / Tri-Service General Hospital, Taiwan, Republic of China
Language: English
Date published: 05/01/2015
Academic Unit: Nephrology; Internal Medicine
Record Identifier: 9984383310102771

Metrics

3 Record Views

7 Times Cited - Web of Science

See more details