Abstract
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.
Highlights
Dietary inorganic phosphate (Pi) is mainly absorbed along the small intestine, and depending on the type of diet absorption represents 40–60% of total ingested phosphate
SLC34A2 has been implicated in the progression of several malignant tumors based on the observation that its mRNA is overexpressed in carcinomas affecting thyroid, lung, ovary, breast, liver, kidney and intestinal tract
The expression profile of NaPi-IIb along the intestinal tract is species specific: the transporter is found in the initial segments of the small intestine in r ats[32,33], whereas its maximal expression in mice has been documented in the ileum[33,34,35]
Summary
Dietary inorganic phosphate (Pi) is mainly absorbed along the small intestine, and depending on the type of diet absorption represents 40–60% of total ingested phosphate (for review see[1]). The effect of these mutations in the sorting and/or activity of the cotransporter has not been analyzed, some of them (including non-sense substitutions or truncations within exons 1–3) are expected to produce severely truncated forms of the protein hardly expected to display any transport activity[16,38] Despite this fact, PAM has been diagnosed in newborns[39] and infants[40] but more often in adult and even elderly persons[41], suggesting that functional inactivation of NaPi-IIb in humans is not lethal. Constitutive ablation of Slc34a2 causes embryonic lethality in m ice[42], though its conditional depletion replicates the human PAM phenotype resulting in impaired alveolar absorption of Pi and microlithiasis[17,43,44] These differences between human and mice raised questions as to whether mice are the proper experimental model from which the role of intestinal NaPi-IIb in Pi balance can be translated to humans. We describe the generation of a rat model with constitutive depletion of Slc34a2
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