Kidney Week

Abstract: FR-PO309

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

Session Information

• Bone and Mineral Metabolism: Basic
  November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Bone and Mineral Metabolism

• 501 Bone and Mineral Metabolism: Basic

Authors

• Ye, Lorena, University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Lorena Ye,

• Jung, Hyun Jun, Johns Hopkins University, Baltimore, Maryland, United States

Hyun Jun Jung,

• Lam, Tracey, University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Tracey Lam,

• Liu, Ivy, University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Ivy Liu,

• Gordon, Andrew, University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Andrew Gordon,

• Marciszyn, Allison L., University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Allison L. Marciszyn,

• Al-bataineh, Mohammad M., University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Mohammad M. Al-bataineh,

• Hughey, Rebecca P., University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Rebecca P. Hughey,

• Welling, Paul A., Johns Hopkins University, Baltimore, Maryland, United States

Paul A. Welling,

• Ray, Evan C., University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Evan C. Ray,

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