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AIM To develop candidate drugs for treating autosomal dominant polycystic kidney disease (PKD) from natural compound library.METHODS An MDCK cyst model, a murine embryonic kidney cyst model and a PKD mouse model were used to screen positive compounds and to evaluate cyst inhibitory activity.Cell viability, proliferation, apoptosis, CFTR function and expression,and signaling pathways in MDCK cells were determined to explore the mechanism of cyst inhibition.RESULTS Curcumin and ginkgolide B were found to significantly inhibit MDCK cyst development in both MDCK cyst model and embryonic kidney cyst model with dose-response relationship.These two compounds neither induced cytotoxicity nor apoptosis in MDCK cells.They failed to affect the chloride transporter CFTR expression and function.Interestingly, curcumin and ginkgolide B inhibited forskolin-promoted cell proliferation and promoted the tubule formation in MDCK cells, which indicates they promotes MDCK cell differentiation.Furthermore,curcumin and ginkgolide B altered Ras/MAPK signaling pathway.Ginkgolide B significantly inhibited cyst enlargement in PKD mouse model.CONCLUSION Both cureumin and ginkgolide B inhibit renal cyst formation and enlargement, suggesting that these natural compounds or their analogues might be developed into novel candidate drugs for polycystic kidney disease.