Ganoderma triterpenes retard renal cyst development by downregulating Ras/MAPK signaling and promoting cell differentiation

Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenetic disease characterized by the progressive development of renal cysts with further need for effective therapy. Here our aim was to investigate the effect of Ganoderma triterpenes (GT) on the development of kidney cysts. Importantly, GT attenuated cyst development in two mouse models of ADPKD with phenotypes of severe cystic kidney disease. Assays for tubulogenesis 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 signaling pathways involved in the pathogenesis of PKD was further investigated by immune blotting. This showed that GT specifically downregulated the activation of the Ras/MAPK signaling pathway both in vitro and in vivo without detectable effect on the mTOR pathway. This mechanism may be involved in GT downregulating intracellular cAMP levels. Screening of 15 monomers purified from GT for their effects on cyst development indicated that CBLZ-7 (ethyl ganoderate C2) had a potent inhibitory effect on cyst development in vitro. Additionally, like GT, CBLZ-7 was able to downregulate forskolin-induced activation of the Ras/MAPK pathway. Thus, GT and its purified monomer CBLZ-7 may be potential therapeutic regents for treating ADPKD.