Novel Calcium Transport Pathways Mediate Intestinal Calcium Absorption Pre‐Weaning

Abstract

Calcium is essential to many vital physiological functions including bone mineralization. Peak bone deposition rate occurs in infancy and maximal bone mineral content is achieved early in adulthood, thereafter bone mass is lost. Maintenance of a positive calcium balance during development is thus essential to achieving optimal bone mass. Calcium homeostasis is mediated by interactions between the intestine, kidneys, and bones. Intestinal absorption occurs by either an active transcellular or passive paracellular pathway. Currently, based on studies in adults the duodenum is thought to be a site of largely transcellular absorption whereas the jejunum and ileum are proposed to mediate exclusively paracellular calcium absorption. There are limited studies on young animals. We therefore set out to describe calcium absorption pathways pre and post weaning. Wildtype FVB/N mice at 7 ages from 1 day to 6 months old were examined. Levels of Trpv6 and CalbD9k mRNA, mediators of transcellular calcium transport, increased six‐fold between two weeks and one month of age in the duodenum with a corresponding increase in CalbindinD9k protein. In the jejunum and ileum, mediators of transcellular transport – Trpv6 (jejunum only), Cav1.3, and CalbD9k – are highly expressed prior to weaning, suggesting novel pathways of calcium absorption during development. Consistent with this, net calcium flux, measured in Ussing chambers, was not different from zero across ileum post weaning. However, we identified significant net absorption in the absence of an electrochemical gradient across ileum prior to weaning. Further, this net absorption was abolished by nifedipine, an L‐type calcium channel blocker. Abundance of Cldn‐2 and ‐15 mRNA, mediators of paracellular absorption, peak at 7 days in the duodenum. In the ileum, Cldn‐2 mRNA peaks at 14 days and decreases 10‐fold by 1 month, whereas Cldn‐15 expression increases 3‐fold from day 14 to 1 month of age. In conclusion, these observations suggest that weaning induces a significant shift from paracellular to transcellular calcium absorption in the duodenum and that there is significant, previously unreported, transcellular calcium absorption from the jejunum and ileum pre weaning mediated by Cav1.3.Support or Funding InformationThis research was funded by the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Stollery Children's Hospital Foundation through the Women and Children's Health Research Institute