Obacunone Retards Renal Cyst Development in Autosomal Dominant Polycystic Kidney Disease by Activating NRF2

• Main Authors: Zhiwei Qiu (Author), Jinzhao He (Author), Guangying Shao (Author), Jiaqi Hu (Author), Xiaowei Li (Author), Hong Zhou (Author), Min Li (Author), Baoxue Yang (Author)
• Format: Book
• Published: MDPI AG, 2021-12-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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 <i>Pkd1</i> knockout mouse (PKD) model, we identified obacunone as a candidate compound for ADPKD drug discovery from a natural antioxidant compound library. <i>In vitro</i> experiments showed that obacunone significantly inhibited cyst formation and expansion of MDCK cysts and embryonic kidney cysts in a dose-dependent manner. <i>In vivo</i>, 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.

Item Description

10.3390/antiox11010038
2076-3921