Aim Autosomal dominant polycystic kidney disease (ADPKD) affects between 1 in 400 to 1000 individuals and is characterized by massive enlargement of fluidfilled cysts of renal tubular origin that compromise normal renal parenchyma and leads to renal failure.Water channel aquaporins (AQPs) are expressed in epithelial cells lining the cysts in ADPKD kidneys, postulating that AQP may be involved in cytogenesis.Here we investigated the role of AQP3 on ADPKD development.Methods and Results To investigate the role of AQP3 on cyst development, we used two ADPKD models, Pkd1flox/flox ;KspCre;AQP3/mice and Pkd1flox/flox ;Mx1 Cre; AQP3/mice.We found that kidney size and cyst number were significantly smaller in AQP3 null PKD mice than in AQP3expressing PKD mice.In matrixgrown MDCK ceils, the AQP3MDCK cell cysts diameter was larger.All these results suggested that AQP3 promoted cyst development.The levels of glucose uptaking, Llactate and ATP were higher in AQP3MDCK, suggesting enhanced glycolysis.The high level of ATP could inhibit AMPactivateing protein kinase (AMPK) and then stimulate ERK/mTOR signaling, and then promoted cell proliferation and fluid secretion.Similarly, AQP3 deficiency lead to downregulation of ERK/mTOR signaling.Further research revealed that AQP3MDCK cells expressed high level of HIF1 α and upregulated GLUT1 expression.Conclusions AQP3upregulated HIF1 α and GLUT1 expression, then promoted glucose uptaking and ATP synthesis.The high level of ATP inhibited AMPK and stimulated ERK/mTOR signaling, and then promoted cell proliferation.Finally, the cyst development was promoted in AQP3expressing cells.These ndings reveal a previously unrecognized role of AQP3in ADPKD and hence may provide a novel therapeutic targets.