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":"drta引起的SLC4A1突变小鼠的尿钠浪费和集尿管功能紊乱。","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":"{\"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}","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}
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.
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.