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

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. Funding: Veterans Affairs Support - 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