O19 Ganoderma triterpenes inhibit kidney cyst development via down-regulating the Ras/MAPK signaling pathway

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenetic disease characterized by progressive development of renal cysts that leads to end stage renal disease. The aim of this study was to investigate the effect of Ganoderma triterpenes (GT), extracts from the natural product Ganoderma lucidum , on the development of kidney cysts. Our study revealed that GT significantly inhibited cyst growth in a dose-dependent manner in an in vitro cystogenesis model and an embryonic kidney cyst model. More importantly, GT was shown to attenuate the progression of cyst and reduce kidney mass in two ADPKD mouse models. To understand the underlying cyst-inhibiting mechanism of GT, a tubulogenesis assay was performed and showed that GT promoted epithelial tubule formation in MDCK cells, suggesting a possible effect on epithelial cell differentiation. The role of GT in regulating key signalling pathways that are involved in the pathogenesis of PKD was further investigated by immunoblotting. Our data revealed that GT specifically downregulated forskolin-induced activation of the Ras/MAPK signalling pathways in MDCK cells without a detectable effect on the mTOR pathway. We further screened 15 monomers that were purified from GT for their effects on inhibiting cyst formation in vitro . We demonstrated that CBLZ-7 (ethyl ganoderate C 2 ) had a potent inhibitory effect on cyst formation in vitro . In addition, like GT, CBLZ-7 was able to downregulate FSK induced activation of the Ras/MAPK pathway. Therefore, our study demonstrated that GT and its purified monomer, CBLZ-7, are potential therapeutic regents for treating cystic kidney diseases.