Evidence for a Downstream Shift in Renal Tubular Reabsorption during Lactation in Mice

Background: Lactation represents an extreme stress for mammalian females, likely requiring substantial physiologic changes in the kidney to adapt to systemic hemodynamic changes and prevent loss of bone minerals. We observe that kidneys of female mice undergo hypertrophy during lactation, and glomerular filtration rate increases. Whole kidney RNAseq demonstrates dramatic changes in transcript abundance, confirming that lactation is associated with physiologic changes. Among transcripts that are markers for discrete tubular segments, transcripts from the proximal convoluted tubule (PCT) and distal convoluted tubule (DCT) are selectively up-regulated, indicating changes in these tubular segments. Hypothesis: We hypothesized that lactation is associated with urinary conservation of bone minerals (Ca, Mg, and Phos), mediated by selective activation of bone mineral transport-related proteins from the DCT and PCT. Methods: Twelve week-old female C57B/6 mice were mated. At post-partum day 2 (P2) resulting litter size was adjusted to four pups. Nulliparous females were included as controls. Spot urine was collected from dams at P11, dams were terminated at P12 when kidneys were flash frozen or fixed, and blood collected. Relative abundance of transport-related proteins was determined by semi-quantitative immunoblot. DCT length was measured following optical clearing of kidney tubules with ethyl cinnamate to allow visualization of TdTomato driven by Pvbcre, a marker of early DCT. Results: Urinary fractional excretion of Ca 2+ , Mg 2+ , and Phos was not changed, however fractional excretion of Li + and Na + increased, suggesting decreased PCT solute reabsorption. Consistent with this, relative abundances of PCT and thick ascending limb transporters NaPi2a, AQP1, NHE3, and NKCC2 were decreased. Among DCT transport-related proteins, calbindin was significantly up-regulated; relative abundance of the Na + / Ca 2+ exchanger, NCC, and phospho-NCC did not change. In kidneys from lactating dams, DCT cells appeared larger, with increased Cyclin D1 expression, and increased segment length, demonstrating DCT hypertrophy. Conclusions: These findings provide evidence that lactation drives a redistribution of tubular solute and volume reabsorption from the proximal to the distal nephron. DCT hypertrophy and increased abundance of DCT bone mineral transporters may compensate for increased GFR and decreased PCT solute reabsorption. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.