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
{"title":"Urinary sodium wasting and disrupted collecting duct function in mice with distal renal tubular acidosis mutations.","authors":"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","doi":"10.1242/dmm.052138","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3000,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128221/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Disease Models & Mechanisms","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1242/dmm.052138","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/5/23 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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.
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.