Developmental Changes in Mechanisms Mediating Phosphate Homeostasis

Abstract

Background Phosphate (Pi) is a multivalent ion involved in a multitude of physiological processes including the formation of hydroxyapatite, the core structural component of bone. Hydroxyapatite formation occurs rapidly early in mammalian development enabling a high rate of bone formation. In the small intestine Pi absorption can occur by a transcellular or passive paracellular pathway. Of note, paracellular ion flux is governed largely by a family of proteins known as claudins, which confer permeability to epithelia. In the kidney, Pi reabsorption occurs entirely through the transcellular route. Pathological perturbations in Pi absorption and reabsorption can result in impaired bone formation and mineralization. We therefore aimed to characterize the normal developmental progression of Pi handling in the gut and kidney to determine mechanisms by which the developing mammal establishes a positive Pi balance. Methods Gene expression was determined by real-time PCR of wild-type mice aged 1, 7 days, 14 and 28 days as well as 2, 3 and 6 months of age. Of note, mice were weaned at 22 days of age. To assess developmental changes in paracellular Pi permeability, small bowel segments were isolated from mice aged 9-14 days old or 15-17 weeks of age and Chloride-Pi diffusion potentials assessed in Ussing chambers. Results The secondary sodium-Pi transporters NaPiIIb in the intestine and NaPiIIa, NaPiIIc in the kidney all showed peak expression levels early in development and proceeded to decrease in their expression levels into adulthood. However, unlike NaPiIIb which consistently displayed high expression before weaning age, NaPiIIa and NaPiIIc expression showed a lifetime low during early suckling followed by maximum lifetime expression at 2 weeks of age. There were no specific changes in claudin expression throughout development. Consistent with this, paracellular Pi permeability did not change between 9-14 days and 15-17 months of age along the intestine. Discussion Our results suggest that the mechanism responsible for establishing a positive Pi balance in young mammals is via increased transcellular absorption/reabsorption, whereas paracellular Pi flux is unlikely a significant contributor.