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 (PKD)

Abstract

In autosomal dominant polycystic kidney disease (ADPKD) there is cyst growth in the kidneys that leads to chronic kidney disease often requiring dialysis or kidney transplantation. There is enhanced aerobic glycolysis (Warburg effect) in the cyst lining epithelial cells 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. Early administration of 2-DG resulted in decreased kidney weight, cyst index, cyst number and cyst size, but no change in kidney function. 2-DG decreased proliferation. a major mediator of cyst growth, of cells lining the cyst. Late administration of 2-DG did not have an effect on cyst growth or kidney function. To determine mechanisms of decreased proliferation, an array of mTOR and autophagy proteins was measured in the kidney. 2-DG suppressed autophagic flux in Pkd1RC/RC kidneys and decreased autophagy proteins, ATG3, ATG5 and ATG12–5. 2-DG had no effect on p-mTOR or p-S6 (mTORC1) and decreased p-AMPK. 2-DG decreased p-4E-BP1, 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. So the role of mTORC2 in cyst growth was determined. Knockout of Rictor (mTORC2) in Pkd1 knockout mice did not change the PKD phenotype. In summary, 2-DG decreases proliferation in cells lining the cyst and decreases cyst growth by decreasing proteins that are known to promote proliferation. In conclusion, the present study reinforces the therapeutic potential of 2-DG for use in patients with ADPKD.