Severe metabolic acidosis causes early lethality in NBC1 W516X knock-in mice as a model of human isolated proximal renal tubular acidosis

Yi Fen Lo, Sung Sun Yang, George Seki, Hideomi Yamada, Shoko Horita, Osamu Yamazaki, Toshiro Fujita, Tomohiko Usui, Jeng Daw Tsai, I. Shing Yu, Shu Wha Lin, Shih Hua Lin

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Abstract

We have identified a novel homozygous nonsense mutation (W516X) in the kidney-type electrogenic sodium bicarbonate cotransporter 1 (NBC1) in a patient with isolated proximal renal tubular acidosis (pRTA). To specifically address the pathogenesis of this mutation, we created NBC1 W516X knock-in mice to match the patient's abnormalities. The expression of NBC1 mRNA and protein in the kidneys of NBC1 W516X/W516X mice were virtually absent, indicating that nonsense-mediated mRNA decay (NMD) is involved in the defective transcription and translation of this mutation. These mice not only recapitulated the phenotypes of this patient with growth retardation, pRTA, and ocular abnormalities, but also showed anemia, volume depletion, prerenal azotemia, and several organ abnormalities, culminating in dehydration and renal failure with early lethality before weaning. In isolated renal proximal tubules, both NBC1 activity and the rate of bicarbonate absorption were markedly reduced. Unexpectedly, there was no compensatory increase in mRNA of distal acid/base transporters. Sodium bicarbonate but not saline administration to these mutant mice markedly prolonged their survival, decreased their protein catabolism and attenuated organ abnormalities. The prolonged survival time uncovered the development of corneal opacities due to corneal edema. Thus, NBC1 W516X/W516X mice with pRTA represent an animal model for metabolic acidosis and may be useful for testing therapeutic inhibition of NMD in vivo.

Original languageEnglish
Pages (from-to)730-741
Number of pages12
JournalKidney international
Volume79
Issue number7
DOIs
Publication statusPublished - 2011 Apr

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Keywords

  • nonsense mutation
  • proximal renal tubular acidosis
  • sodium bicarbonate cotransporter

ASJC Scopus subject areas

  • Nephrology

Cite this

Lo, Y. F., Yang, S. S., Seki, G., Yamada, H., Horita, S., Yamazaki, O., Fujita, T., Usui, T., Tsai, J. D., Yu, I. S., Lin, S. W., & Lin, S. H. (2011). Severe metabolic acidosis causes early lethality in NBC1 W516X knock-in mice as a model of human isolated proximal renal tubular acidosis. Kidney international, 79(7), 730-741. https://doi.org/10.1038/ki.2010.523