Alexander, R. T. | bioRxiv Science

bioRxiv2024

Urinary Sodium Wasting and Disrupted Collecting Duct Function in Mice with dRTA-Causing SLC4A1 Mutations

Distal renal tubular acidosis (dRTA) results in metabolic acidosis due to impaired urinary acidification and can also result in an unexplained urinary sodium-wasting phenotype. Here, we report the generation and characterization of a novel dRTA mutant mouse line, Ae1 L919X knockin (KI). Homozygous L919X KI mice exhibit typical dRTA features including a reduced ability to acidify urine in response to an acid load. This renal acidification defect was associated with a reduced number of Ae1-positive type A intercalated cells. To assess whether these mice exhibit urinary sodium-wasting as seen in some dRTA patients, homozygous KI L919X 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 -10b, suggesting a compensatory paracellular pathway in the loop of Henle. Consistent with data from human patients, L919X KI mice displayed a milder phenotype than R607H KI mice. Our findings reveal that both mouse strains are appropriate models for dRTA with a urinary salt-wasting phenotype and a compensatory up-regulation of the paracellular pathway in the ascending limb of the loop of Henle.

physiology↗

bioRxiv2021

Differential activation of parathyroid and renal Ca2+-sensing receptors underlies the renal phenotype in autosomal dominant hypocalcemia 1

BackgroundParathyroid Ca2+-sensing receptor (CaSR) activation inhibits parathyroid hormone (PTH) release, while activation of CaSRs in kidneys and intestine attenuates local transepithelial Ca2+ transport. In patients with autosomal dominant hypocalcemia 1 (ADH1) due to activating CASR mutations, treatment of symptomatic hypocalcemia can be complicated by treatment-induced hypercalciuria, resulting in nephrocalcinosis and renal insufficiency. Although CaSRs throughout the body are activated by increased extracellular Ca2+ concentrations, it is not understood why some ADH1 patients have reduced PTH, but not hypercalciuria at presentation, despite CaSR expression in both kidney and parathyroid. MethodsActivation of the CaSR was studied in mouse models and a ADH1 patient. In vitro CaSR activation was studied in HEK293 cells. ResultsMice with a gain-of-function mutation in Casr are hypocalcemic with reduced plasma PTH levels. However, renal CaSRs are not activated as indicated by normal urinary calcium handling and unaltered renal Cldn14 expression. Activation of renal CaSRs only occurred after increasing plasma Ca2+ levels. Similarly, calcimimetic administration to wildtype mice induced hypocalcemia without activating renal CaSRs. Moreover, significant hypercalciuria was not observed in an ADH1 patient until blood Ca2+ was normalized. In vitro experiments suggest that increased CaSR levels in the parathyroid relative to the kidney contribute tissue-specific CaSR activation thresholds. ConclusionHere we delineate tissue-specific CaSR activation thresholds, where parathyroid CaSR overactivity can reduce plasma Ca2+ to levels insufficient to activate renal CaSRs, even with overactivating mutations. These findings may aid in the management of ADH1 patients.

physiology↗