Regulation of Calcium Transport Pathways in Kidney and Intestine During Lactation

Abstract

Significant alterations in maternal calcium balance occur postpartum during lactation. Demineralization of the skeleton mobilizes calcium, in order to supply this mineral to the neonate via breast milk. Changes in intestinal and renal calcium transport processes also promote this. However, the specific molecular alterations in transcellular and paracellular calcium transport pathways across renal and intestinal epithelia during lactation have not been fully delineated. To ascertain which changes occur during lactation, female mice were divided into 3 groups, non‐pregnant controls, lactating mice with litters maintained for 12 days after birth, or mice undergoing involution with litters removed after birth and maintained for 12 days. Induction of lactogenesis was confirmed histologically in mammary fat pads. Bodyweight increased in lactating mice as did urinary volume, measured during 9‐hr collections performed on day 11. Both total urinary excretion and fractional excretion of calcium and magnesium were elevated during lactation. Enlargement of the intestinal tract was confirmed visually in lactating animals. Renal 1‐alpha hydroxylase and 24‐OHase mRNA expression increased dramatically. This was accompanied by significant increases in the gene expression of Trpv6 and Calbindin‐D9K in duodenum and proximal large bowel of lactating mice. No significant alterations in the calcium permeable claudins (−2, −12 or −15) were observed in any intestinal segments. A similar gene expression profile was observed in kidney, which showed no change in claudins (−2, −12, −14, −15, −16 or −19), while marked increases in Trpv5 and Calbindin‐D28K were observed. Increased Calbindin‐D28K protein expression was found by immunohistochemical analysis, while no changes in claudin‐2 were noted, in line with observations from mRNA expression analysis. In conclusion, proteins driving transcellular calcium transport pathways increase during lactation, likely due to increased Vitamin D dependent‐stimulation, while proteins mediating paracellular transport appear unchanged. Increased urinary mineral excretion can be explained on the basis of intestinal hyperabsorption and bone demineralization, although selective calcium uptake is maintained in kidney.Support or Funding InformationThis work was funded by grants from the Novo Nordisk Foundation (HD), the Carlsberg Foundation (HD), the A.P. Møller Foundation (HD), the Lundbeck foundation (HD), the Kidney Foundation of Canada (RTA), and the Canadian Institute of Health Research (CIHR) (RTA). A Clinician Scientist Award from CIHR and an Alberta Innovates Health Solutions Clinical Investigator Award supports Dr. R.T. Alexander.