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.