drta引起的SLC4A1突变小鼠的尿钠浪费和集尿管功能紊乱。

IF 3.3 3区 医学 Q2 CELL BIOLOGY
Disease Models & Mechanisms Pub Date : 2025-05-01 Epub Date: 2025-05-23 DOI:10.1242/dmm.052138
Priyanka Mungara, Kristina MacNaughton, A K M Shahid Ullah, Grace Essuman, Forough Chelangarimiyandoab, Rizwan Mumtaz, J Christopher Hennings, Christian A Hübner, Dominique Eladari, R Todd Alexander, Emmanuelle Cordat
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引用次数: 0

摘要

远端肾小管酸中毒(dRTA)由于尿酸化受损导致代谢性酸中毒,并可导致不明原因的尿钠消耗表型。我们报道了一种新的dRTA突变小鼠系Ae1 L919X knockin (KI)的产生和表征。纯合子L919X KI小鼠表现出典型的dRTA特征,包括在酸负荷下尿液酸化能力降低。这种肾酸化缺陷与ae1阳性的a型插层细胞数量减少有关。为了评估这些小鼠是否表现出尿钠消耗,纯合子KI L919X和先前描述的R607H KI小鼠被喂食无盐酸饮食。与人类患者一致,两种小鼠品系都表现出尿钠流失。此外,我们还发现紧密连接蛋白claudin-4和-10b的表达增加,表明存在代偿性细胞旁通路。与人类患者的数据一致,L919X KI小鼠比R607H KI小鼠表现出更温和的表型。我们的研究结果表明,这两种小鼠品系都是具有尿盐消耗表型和细胞旁通路代偿上调的dRTA的合适模型。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Urinary sodium wasting and disrupted collecting duct function in mice with distal renal tubular acidosis mutations.

Distal renal tubular acidosis (dRTA) results in metabolic acidosis owing to impaired urinary acidification and can result in an unexplained urinary sodium-wasting phenotype. We report the generation and characterization of a novel dRTA mutant mouse line, Ae1 L919X knock-in (KI). Homozygous L919X KI mice exhibit typical dRTA features, including reduced ability to acidify urine in response to an acid load. This renal acidification defect was associated with a reduced number of kAE1-positive type A intercalated cells. To assess whether these mice exhibit urinary sodium wasting, homozygous L919X KI mice and the previously described R607H KI mice were fed a salt-depleted acid diet. In line with human patients, both mouse strains exhibited urinary sodium loss. Additionally, we identified increased expression of tight junction proteins claudin 4 and claudin 10b, suggesting a compensatory paracellular pathway. Consistent with data from human patients, L919X KI mice displayed a milder phenotype than that of R607H KI mice. Our findings reveal that both mouse strains are appropriate models for dRTA with a urinary salt-wasting phenotype and compensatory upregulation of the paracellular pathway.

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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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