Abstract: TH-PO320
Dietary Potassium Restriction Activates a Proliferative Cell Population to Remodel the Distal Convoluted Tubule
Session Information
- Fluid, Electrolyte, and Acid-Base Disorders: Basic
November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Fluid‚ Electrolyte‚ and Acid-Base Disorders
- 1001 Fluid‚ Electrolyte‚ and Acid-Base Disorders: Basic
Authors
- Su, Xiao-Tong, Oregon Health & Science University, Portland, Oregon, United States
- Cornelius, Ryan J., Oregon Health & Science University, Portland, Oregon, United States
- McCormick, James A., Oregon Health & Science University, Portland, Oregon, United States
- Yang, Chao-Ling, Oregon Health & Science University, Portland, Oregon, United States
- Ellison, David H., Oregon Health & Science University, Portland, Oregon, United States
- Nelson, Jonathan W., Oregon Health & Science University, Portland, Oregon, United States
Background
Low dietary K intake has adverse health effects. Dietary K restriction rapidly activates a potassium switch in the distal nephron to maintain homeostasis by reducing K excretion at the expense of sodium retention. When prolonged, dietary K stress leads to profound remodeling of distal convoluted tubule (DCT), making chronic adaptation largely structural. Knepper and colleagues recently described a unique cell population in the DCT that expresses proliferative markers. Here, we tested whether dietary K restriction activates this population rapidly, and plays a central role in chronic K balance.
Methods
Female NCC (Na-Cl cotransporter)-Cre-INTACT (Isolation of Nuclei TAgged in specific Cell Types, which fluorescently labels nuclei) mice were provided either control (NK) or K deficient (KD) diet for 4 days and kidneys were harvested for targeted single-nucleus RNA-seq (NovaSeq) (3 mice per diet).
Results
Unbiased clustering and UMAP visualization revealed 12 clusters, with most cells from the DCT (78%) indicating the success of the enrichment process. Among those, 70% were from DCT1 and 30% from DCT2. There was a small population (<1%) enriched in proliferation-related genes, such as Top2a, Cenpp, and Mki67.KD resulted in a 6-fold increase in the number of proliferating cells. To determine the origin of this population, we performed trajectory analysis, which allows us to order each cell according to its progress along a learned trajectory, expressed as Pseudotime, to indicate the distance between a cell and trajectory start. This analysis indicated that the proliferating population arises from DCT1 cells. Four-day KD treatment also decreased the ENaC (Scnn1g) and kallikrein (Klk1) expression in DCT2, indicating that some DCT2 cells may reprogram to retain potassium in response to the short-term KD. We have shown previously that KD increases calciuresis; here, KD also decreased expression of calcium-handling genes, such as Slc8a1, Calb and Vdr.
Conclusion
Our results suggest that a unique population of cells originating from DCT1 has the potential to proliferate during KD leading to remodeling. DCT cells also reprogram transcriptionally to maintain electrolyte balance, likely contributing to the adverse effects of low potassium intake.
Funding
- NIDDK Support