Obacunone Retards Renal Cyst Development in Autosomal Dominant Polycystic Kidney Disease by Activating NRF2
Zhiwei Qiu,
Jinzhao He,
Guangying Shao,
Jiaqi Hu,
Xiaowei Li,
Hong Zhou,
Min Li,
Baoxue Yang
Affiliations
Zhiwei Qiu
State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
Jinzhao He
State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
Guangying Shao
State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
Jiaqi Hu
State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
Xiaowei Li
State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
Hong Zhou
State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
Min Li
State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
Baoxue Yang
State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disease characterized by progressive enlargement of fluid-filled cysts derived from renal tubular epithelial cells, which has become the fourth leading cause of end-stage renal diseases. Currently, treatment options for ADPKD remain limited. The purpose of this study was to discover an effective therapeutic drug for ADPKD. With virtual screening, Madin-Darby canine kidney (MDCK) cyst model, embryonic kidney cyst model and kidney-specific Pkd1 knockout mouse (PKD) model, we identified obacunone as a candidate compound for ADPKD drug discovery from a natural antioxidant compound library. In vitro experiments showed that obacunone significantly inhibited cyst formation and expansion of MDCK cysts and embryonic kidney cysts in a dose-dependent manner. In vivo, obacunone treatment significantly reduced the renal cyst development in PKD mice. Western blot and morphological analysis revealed that obacunone served as a NRF2 activator in ADPKD, which suppressed lipid peroxidation by up-regulating GPX4 and finally restrained excessive cell proliferation by down-regulating mTOR and MAPK signaling pathways. Experimental data demonstrated obacunone as an effective renal cyst inhibitor for ADPKD, indicating that obacunone might be developed into a therapeutic drug for ADPKD treatment.
