Abstract: TH-PO449
Early Treatment with 2-Deoxy-D-Glucose Reduces Proliferative Proteins in the Kidney and Slows Cyst Growth in a Hypomorphic Pkd1 Mouse Model of Autosomal Dominant Polycystic Kidney Disease
Session Information
- Cystic Kidney Diseases: Clinical Assessment and Therapeutic Directions
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic
Authors
- Atwood, Daniel, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- He, Zhibin, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Miyazaki, Makoto, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Edelstein, Charles L., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
Background
There is enhanced aerobic glycolysis (Warburg effect) in the cyst lining epithelial cells in ADPKD that contributes to cyst growth. The glucose mimetic, 2-Deoxy-d-glucose (2-DG) inhibits glycolysis. The effect of early and late administration of 2-DG on cyst growth and kidney function was determined in Pkd1RC/RC mice, a hypomorphic PKD model orthologous to human disease.
Methods
Mice were treated with 2-DG (100 mg/kg/d IP) from 50-120 (Early treatment) or 150 to 350 days old (Late treatment). An array of mTOR and autophagy proteins was measured in the kidney by immunoblot analysis. Cre-lox technology was used to Pkd1, Rictor double knockout mice. Proliferation measured by PCNA IHC
Results
Early administration of 2-DG decreased cyst indices (See table). 2-DG decreased proliferation of cells lining the cyst. Late administration of 2-DG had no effect on cyst growth (See Table). 2-DG suppressed autophagic flux in kidneys evidenced by no increase in LC3-II 2 hrs after IP injection of bafilomycin and a decrease in autophagy proteins, ATG3, ATG5 and ATG12-5. 2-DG had no effect on p-mTOR or p-S6 (mTORC1). 2-DG decreased both functional p-4E-BP1 isoforms, p-c-Myc and p-ERK that are known to promote proliferation and cyst growth in PKD. 2-DG decreased p-AKTS473, a marker of mTORC2. However, knockout of Rictor (mTORC2) in Pkd1 knockout mice did not change the PKD phenotype.
Conclusion
In summary, 2-DG decreases proliferation in cells lining the cyst and decreases cyst growth by decreasing proteins that are known to promote proliferation. The present study reinforces the therapeutic potential of 2-DG for use in patients with ADPKD.
| VEH | 2-DG (50-120) | VEH | 2-DG (150-350) | |
| BW (g) | 26 | 26 | 25 | 26 |
| KW/BW (%) | 2.4 | 2.0* | 2.9 | 2.7 |
| Index (%) | 8.8 | 4.1* | 19 | 18 |
| Cyst # | 211 | 161* | 441 | 401 |
| BUN (mg/dL) | 27 | 25 | 35 | 33 |
| HW/BW (%) | 0.5 | 0.5 | 0.6 | 0.5 |
| p/t-ERK (RDU) | 0.7 | 0.3* | ||
| p/t-c-Myc (RDU) | 0.5 | 0.2* | ||
| p/t-4E-BP1 (RDU) | 0.5/0.7* | 0.2/0.3* | ||
*P<0.05. RDU=relative densitometry units on immunoblot
Funding
- Veterans Affairs Support