# Absence of claudin-3 does not alter intestinal absorption of phosphate in mice

## TL;DR

This study shows that claudin-3 does not significantly affect phosphate absorption in mice intestines, but may influence calcitriol levels.

## Contribution

The study challenges the proposed role of claudin-3 in intestinal phosphate absorption and suggests a new role in regulating calcitriol.

## Key findings

- Cldn3-deficient mice showed no differences in phosphate absorption compared to wildtype mice.
- Cldn3-deficient mice had reduced urinary calcium and increased plasma calcitriol under high-phosphate diets.
- Intestinal expression of claudin-7 was unchanged in Cldn3-deficient mice.

## Abstract

Intestinal absorption of phosphate is bimodal, consisting of a transcellular pathway and a poorly characterized paracellular mode, even though the latter one contributes to the bulk of absorption under normal dietary conditions. Claudin-3 (Cldn3), a tight junction protein present along the whole intestine in mice, has been proposed to tighten the paracellular pathway for phosphate. The aim of this work was to characterize the phosphate-related phenotype of Cldn3-deficient mice. Cldn3-deficient mice and wildtype littermates were fed standard diet or challenged for 3 days with high dietary phosphate. Feces, urine, blood, intestinal segments and kidneys were collected. Measurements included fecal, urinary, and plasma concentrations of phosphate and calcium, plasma levels of phosphate-regulating hormones, evaluation of trans- and paracellular phosphate transport across jejunum and ileum, and analysis of intestinal phosphate and calcium permeabilities. Fecal and urinary excretion of phosphate as well as its plasma concentration was similar in both genotypes, under standard and high-phosphate diet. However, Cldn3-deficient mice challenged with high dietary phosphate had a reduced urinary calcium excretion and increased plasma levels of calcitriol. Intact FGF23 concentration was also similar in both groups, regardless of the dietary conditions. We found no differences either in intestinal phosphate transport (trans- or paracellular) and phosphate and calcium permeabilities between genotypes. The intestinal expression of claudin-7 remained unaltered in Cldn3-deficient mice. Our data do not provide evidence for a decisive role of Cldn3 for intestinal phosphate absorption and phosphate homeostasis. In addition, our data suggest a novel role of Cldn3 in regulating calcitriol levels.

The online version contains supplementary material available at 10.1007/s00424-024-02998-x.