Severe metabolic acidosis causes early lethality in NBC1 W516X knock-in mice as a model of human isolated proximal renal tubular acidosis
Severe metabolic acidosis causes early lethality in NBC1 W516X knock-in mice as a model of human isolated proximal renal tubular acidosis
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DOI：
10.1038/ki.2010.523
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发表时间：
2011-04-01
影响因子：
19.6
通讯作者：
Lin, Shih-Hua
中科院分区：
文献类型：
--
作者：
Lo, Yi-Fen;Yang, Sung-Sun;Lin, Shih-Hua
我们在一例孤立性肾近端小管酸中毒（pRTA）患者的肾型电致碳酸氢钠共转运蛋白1 （NBC1）中发现了一种新的纯合无意义突变（W516X）。为了明确这种突变的发病机制，我们创建了NBC1 W516X敲入小鼠来匹配患者的异常。NBC1（W516X/W516X）小鼠肾脏中NBC1 mRNA和蛋白的表达几乎不存在，表明无义介导的mRNA衰变（NMD）参与了该突变的缺陷转录和翻译。这些小鼠不仅重现了该患者的表型，包括生长迟缓、pRTA和眼部异常，而且还表现出贫血、体积减少、肾氮质血症和几个器官异常，最终导致脱水和肾功能衰竭，并在断奶前早期死亡。在离体肾近端小管中，NBC1活性和碳酸氢盐吸收率均明显降低。出乎意料的是，远端酸/碱转运体的mRNA没有代偿性增加。给这些突变小鼠碳酸氢钠而不是生理盐水显著延长了它们的生存时间，降低了它们的蛋白质分解代谢，减轻了器官异常。存活时间的延长揭示了角膜水肿导致的角膜混浊的发生。因此，含有pRTA的NBC1（W516X/W516X）小鼠代表了代谢性酸中毒的动物模型，可能用于体内测试NMD的治疗性抑制。国际肾脏杂志（2011）79,730-741；doi: 10.1038 / ki.2010.523;2011年1月12日在线发布
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. Kidney International (2011) 79, 730-741; doi: 10.1038/ki.2010.523; published online 12 January 2011