Constitutive depletion of Slc34a2/NaPi-IIb in rats causes perinatal mortality

• Published in: Scientific reports Vol. 11; no. 1; p. 7943
• Main Authors: Pastor-Arroyo, Eva Maria, Rodriguez, Josep M. Monné, Pellegrini, Giovanni, Bettoni, Carla, Levi, Moshe, Hernando, Nati, Wagner, Carsten A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.04.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/443; 631/443/272; 631/443/319; 631/443/810; Ablation; Absorption; Animal models; Animals; Animals, Newborn; Body Weight; Calcium - blood; Calcium - urine; Cardiovascular diseases; Cell culture; Creatinine - urine; CRISPR; Diet; Embryo, Mammalian - pathology; Epithelial cells; Feces; Feces - chemistry; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors - blood; Food; Heterozygote; Homozygosity; Homozygote; Humanities and Social Sciences; Hyperphosphatemia; Intestinal absorption; Intestine; Kidneys; Lethality; Male; Mice; Mortality; multidisciplinary; Mutation; Organ Specificity; Phosphates - blood; Phosphates - metabolism; Phosphates - urine; Physiology; Proteins; Rats; Risk factors; Science; Science (multidisciplinary); Small intestine; Sodium-Phosphate Cotransporter Proteins, Type IIb - metabolism; Survival Analysis; Thyroid gland
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-86874-z

Absorption of dietary phosphate (Pi) across intestinal epithelia is a regulated process mediated by transcellular and paracellular pathways. Although hyperphosphatemia is a risk factor for the development of cardiovascular disease, the amount of ingested Pi in a typical Western diet is above physiological needs. While blocking intestinal absorption has been suggested as a therapeutic approach to prevent hyperphosphatemia, a complete picture regarding the identity and regulation of the mechanism(s) responsible for intestinal absorption of Pi is missing. The Na + /Pi cotransporter NaPi-IIb is a secondary active transporter encoded by the Slc34a2 gene. This transporter has a wide tissue distribution and within the intestinal tract is located at the apical membrane of epithelial cells. Based on mouse models deficient in NaPi-IIb, this cotransporter is assumed to mediate the bulk of active intestinal absorption of Pi. However, whether or not this is also applicable to humans is unknown, since human patients with inactivating mutations in SLC34A2 have not been reported to suffer from Pi depletion. Thus, mice may not be the most appropriate experimental model for the translation of intestinal Pi handling to humans. Here, we describe the generation of a rat model with Crispr/Cas-driven constitutive depletion of Slc34a2 . Slc34a2 heterozygous rats were indistinguishable from wild type animals under standard dietary conditions as well as upon 3 days feeding on low Pi. However, unlike in humans, homozygosity resulted in perinatal lethality.