[Inositol 1,4,5-triphosphate receptor 3 promotes renal cyst development in autosomal dominant polycystic kidney disease].

The purpose of the present study was to determine the role of inositol 1,4,5-trisphosphate receptor 3 (IPR3) in renal cyst development in autosomal dominant polycystic kidney disease (ADPKD). 2-aminoethoxy-diphenyl borate (2-APB) and shRNA were used to suppress the expression of IPR3. The effect of IPR3 on cyst growth was investigated in Madin-Darby canine kidney (MDCK) cyst model, embryonic kidney cyst model and kidney specific Pkd1 knockout (PKD) mouse model. The underlying mechanism of IPR3 in promoting renal cyst development was investigated by Western blot and immunofluorescence staining. The results showed that the expression level of IPR3 was significantly increased in the kidneys of PKD mice. Inhibiting IPR3 by 2-APB or shRNA significantly retarded cyst expansion in MDCK cyst model and embryonic kidney cyst model. Western blot and immunofluorescence staining results showed that hyperactivated cAMP-PKA signaling pathway in the growth process of ADPKD cyst promoted the expression of IPR3, which was accompanied by a subcellular redistribution process in which IPR3 was translocated from endoplasmic reticulum to intercellular junction. The abnormal expression and subcellular localization of IPR3 further promoted cyst epithelial cell proliferation by activating MAPK and mTOR signaling pathways and accelerating cell cycle. These results suggest that the expression and subcellular distribution of IPR3 are involved in promoting renal cyst development, which implies IPR3 as a potential therapeutic target of ADPKD.