Therapeutic effect of prenatal alkalization and PTC124 in Na + /HCO 3 - Cotransporter 1 p.W516∗ knock-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

Research output: Contribution to journalArticle

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Abstract

We created Na + /HCO 3 - 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). Mutation-specific 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 wild-type 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, P<0.05) 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.

Original languageEnglish
Pages (from-to)374-381
Number of pages8
JournalGene Therapy
Volume22
Issue number5
DOIs
Publication statusPublished - 2015 May 9
Externally publishedYes

Fingerprint

Therapeutic Uses
Gentamicins
Therapeutics
Histology
Renal Tubular Acidosis
Kidney
Messenger RNA
Nonsense Codon
Alkalies
Bicarbonates
Acidosis
Biochemistry
Weight Gain
Proteins
Body Weight
Urine
Mutation
Acids
Serum

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Fang, Y. W., Yang, S. S., Chau, T., Nakamura, M., Yamazaki, O., Seki, G., ... Lin, S. H. (2015). Therapeutic effect of prenatal alkalization and PTC124 in Na + /HCO 3 - Cotransporter 1 p.W516∗ knock-in mice. Gene Therapy, 22(5), 374-381. https://doi.org/10.1038/gt.2015.7

Therapeutic effect of prenatal alkalization and PTC124 in Na + /HCO 3 - Cotransporter 1 p.W516∗ knock-in mice. / Fang, Y. W.; Yang, S. S.; Chau, T.; Nakamura, M.; Yamazaki, O.; Seki, G.; Yamada, H.; Hsu, H. M.; Cheng, C. J.; Lin, S. H.

In: Gene Therapy, Vol. 22, No. 5, 09.05.2015, p. 374-381.

Research output: Contribution to journalArticle

Fang, YW, Yang, SS, Chau, T, Nakamura, M, Yamazaki, O, Seki, G, Yamada, H, Hsu, HM, Cheng, CJ & Lin, SH 2015, 'Therapeutic effect of prenatal alkalization and PTC124 in Na + /HCO 3 - Cotransporter 1 p.W516∗ knock-in mice', Gene Therapy, vol. 22, no. 5, pp. 374-381. https://doi.org/10.1038/gt.2015.7
Fang, Y. W. ; Yang, S. S. ; Chau, T. ; Nakamura, M. ; Yamazaki, O. ; Seki, G. ; Yamada, H. ; Hsu, H. M. ; Cheng, C. J. ; Lin, S. H. / Therapeutic effect of prenatal alkalization and PTC124 in Na + /HCO 3 - Cotransporter 1 p.W516∗ knock-in mice. In: Gene Therapy. 2015 ; Vol. 22, No. 5. pp. 374-381.
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