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Published on: September 1, 2015
Obacunone Retards Renal Cyst Development in Autosomal Dominant Polycystic Kidney Disease by Activating NRF2
Zhiwei Qiu1, Jinzhao He1, Guangying Shao1
1State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
Abstract:
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.
Insights
Obacunone effectively inhibits cyst growth in autosomal dominant polycystic kidney disease (ADPKD) models. This natural compound acts as a NRF2 activator, offering a promising new therapeutic avenue for ADPKD treatment.
Area of Science:
- Nephrology
- Pharmacology
- Molecular Biology
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder causing kidney failure.
- Current ADPKD treatments are limited, necessitating novel therapeutic strategies.
Purpose of the Study:
- To identify a potential therapeutic drug for ADPKD from a natural antioxidant compound library.
Main Methods:
- Virtual screening and various cyst models (MDCK, embryonic kidney, PKD mouse) were employed.
- In vitro and in vivo experiments assessed obacunone's efficacy.
- Western blot and morphological analyses elucidated the underlying molecular mechanisms.
Main Results:
- Obacunone significantly inhibited cyst formation and expansion in both in vitro and in vivo models.
- Obacunone functions as a NRF2 activator, suppressing lipid peroxidation via GPX4 upregulation.
- It also restrained cell proliferation by downregulating mTOR and MAPK signaling pathways.
Conclusions:
- Obacunone demonstrates potent renal cyst inhibitory effects in ADPKD.
- This compound shows potential for development into an effective therapeutic agent for ADPKD.
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