Combination of curcumin and ginkgolide B inhibits cystogenesis by regulating multiple signaling pathways.

Abstract

Autosomal dominant polycystic kidney disease (ADPKD), a common disease with a high incidence ratio of between 1/400 and 1/1,000 individuals, often results in kidney failure and even mortality. However, there are relatively few effective treatments available, and treatment is limited to lifelong hemodialysis or kidney transplant. Our previous studies have reported that curcumin (Cur) and ginkgolide B (GB) inhibited cystogenesis by regulating the Ras/ERK MAPK signaling pathway. In the present study, it was hypothesized that Cur and GB may have a synergistic effect on the inhibition of cystogenesis, and their synergistic effect may be the result of regulation of multiple signaling pathways. To assess this hypothesis, an in vitro Madin-Darby canine kidney (MDCK) cyst model and an in vivo kidney-specific polycystin 1 transient receptor potential channel interacting (Pkd1) knockout mouse model were established to observe the effects of the combination of Cur and GB. The cysts exposed to Cur, GB and Cur combined with GB became small thick-walled cysts, small thin-walled cysts and round shaped cell colonies, respectively. The combination of Cur and GB was more effective compared with either treatment alone in inhibiting cystogenesis. Additionally, to the best of our knowledge, the present study was the first to demonstrate the synergistic effect of Cur and GB on the inhibition of cystogenesis in Pkd1 knockout mice. Cur may have mediated its anti-cyst effects by blocking EGFR/ERK1/2, JNK and PI3K/mTOR signaling pathways, while GB may have inhibited cystogenesis via the downregulation of the EGFR/ERK1/2, JNK and p38 signaling pathways. These results provide a proof-of-concept for application of the combination of Cur and GB in inhibiting cystogenesis in ADPKD.