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Abstract: FR-PO309

Lactating Kidneys Upregulate Expression of Cell Proliferation Genes and TRPM6 in the Distal Convoluted Tubule (DCT), Suggesting DCT Hyperplasia 

Session Information

Category: Bone and Mineral Metabolism

  • 501 Bone and Mineral Metabolism: Basic

Authors

  • Ye, Lorena, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Jung, Hyun Jun, Johns Hopkins University, Baltimore, Maryland, United States
  • Lam, Tracey, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Liu, Ivy, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Gordon, Andrew, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Marciszyn, Allison L., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Al-bataineh, Mohammad M., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Hughey, Rebecca P., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Welling, Paul A., Johns Hopkins University, Baltimore, Maryland, United States
  • Ray, Evan C., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Background

Lactating females provide large quantities of minerals to nursing offspring, including Ca2+, but also Mg2+. Lactation-associated Ca2+ conservation is stimulated when parathyroid hormone (PTH)-related peptide from the mammary gland activates renal tubular PTH receptors, promoting Ca2+ channel expression. However, mechanisms responsible for Mg2+ conservation are not described.

Methods

Female C57Bl/6 mice were mated and monitored for parturition. To normalize milk-demand, litters were culled to 4 pups at post-partum day 2 (P2). Urine was collected from P12 or nulliparous females. Mice were euthanized, and blood and kidneys harvested. Bulk RNA-Seq was performed in whole kidneys.

Results

Lactation reduced urinary Ca2+ and Mg2+, even though circulating Ca2+ and Mg2+ were similar or higher, consistent with increased tubular reabsorption.

We asked whether acute PTH receptor (PTHR) stimulation reduced urinary Mg2+ excretion. Acute treatment of animals with 1-34 PTH accelerated phosphorus excretion and delayed Ca2+ excretion, as expected, but had no net effect on Mg2+ excretion.

Transcriptomic analysis in kidneys from lactating dams revealed increased mRNA encoding the Mg2+-selective ion channel, TRPM6, exclusively expressed in the distal convoluted tubule (DCT). Transcript levels of proteins involved in paracellular transport (claudins 10, 16, and 19) were not significantly different.

Kidneys from lactating dams were heavier, suggesting tissue hypertrophy. Segment-specific transcripts from the proximal convoluted tubule (PCT) and DCT were up-regulated, consistent with an increase in cell number in these tubule segments. Transcripts encoding numerous cell cycle-associated proteins also increased, including CDC20, cyclin-dependent kinase 1, cyclin D1, and cyclin D3. Cyclin D1 protein abundance also increased. In the early DCT, where TRPM6 is expressed, more cells from lactating than nulliparous females stained positive for cyclin D1.

Conclusion

These suggest that DCT hyperplasia may contribute to lactation-associated conservation of essential minerals.

Funding

  • NIDDK Support