Aquaporin 3 is a potential drug target for polycystic kidney disease

Aim Autosomal dominant polycystic kidney disease （ADPKD） affects between 1 in 400 to 1000 indi- viduals and is characterized by massive enlargement of fluid-filled cysts of renal tubular origin that compromise nor- mal 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 investiga- ted the role of AQP3 on ADPKD development. Methods and Results To investigate the role of AQP3 on cyst de- velopment, we used two ADPKD models, Pkdlflox/flox;Ksp-Cre;AQP3-/- mice and Pkdlflox/flox;MxlCre; AQP3-/- mice. We found that kidney size and cyst number were significantly smaller in AQP3 null PKD mice than in AQP3- expressing PKD mice. In matrix-grown MDCK cells, the AQP3-MDCK cell cysts diameter was larger. All these re- sults suggested that AQP3 promoted cyst development. The levels of glucose up-taking, L-lactate and ATP were higher in AQP3-MDCK, suggesting enhanced glycolysis. The high level of ATP could inhibit AMP-activateing pro- tein kinase （AMPK） and then stimulate ERIL/mTOR signaling, and then promoted cell proliferation and fluid se- cretion. Similarly, AQP3 deficiency lead to down-regulation of ERIL/mTOR signaling. Further research revealed that AQP3-MDCK cells expressed high level of HIF1 a and up-regulated GLUT1 expression. Conclusions AQP3 up-regulated HIFlα and GLUT1 expression, then promoted glucose up-taking 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 AQP3-expressing cells. These ndings reveal a previously unrecognized role of AQP3 in ADPKD and hence may provide a novel therapeutic targets.