Bao-xue YANG,Li-min SU,Li-ying LIU,Hong ZHOU,Ruo-yun CHEN

(1.State Key Laboratory of Natural and Biomimetic Drugs,Department of Pharmacology,School of Basic Medical Sciences,Peking University,Beijing 100191,China;2.State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China)

T2-30

Ganoderma triterpenes slow cyst growth in polycystic kidney disease

Bao-xue YANG1,Li-min SU1,Li-ying LIU2,Hong ZHOU1,Ruo-yun CHEN2

(1.State Key Laboratory of Natural and Biomimetic Drugs,Department of Pharmacology,School of Basic Medical Sciences,Peking University,Beijing 100191,China;2.State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China)

OBJECTIVEAutosomal dominant polycystic kidney disease(ADPKD)is a common inherited disease with a high morbidity around 1/1000-1/400,characterized by progressive enlargement of fluid-filled cysts derived from renal tubular epithelial cells.Massive cysts gradually compress renal parenchyma destroying normal renal structures and compromising renal functions.Unfortunately,it will cause end-stage renal disease in most of the patients but without effective therapy now,who have to live on hemodialysis or kidney transplantation.Based on this present situation,it is of great significance to find early intervention to inhibit renal cyst development.The projective of this study was to investigate whether Ganoderma triterpenes(GT)can inhibit renal cyst development and study the related mechanism.METHODS andRESULTSFirst,we used MDCK cyst model,cultivated MDCK cells in vitro to form fluid-filled cysts surrounded by monolayer cells.GT inhibited MDCK cyst formation significantly,and inhibited cyst enlargement dose-dependently proving GT cyst inhibition in vitro.Then we used an embryonic kidney cyst model,wile-type mice kidneys were taken out on embryonic day 13.5 to form renal cysts stimulated with 8-Br-cAMP.GT inhibited embryonic kidney cyst development significantly in a dosedependent and reversible manner proving GT cyst inhibition at organ level.Furthermore,we used two ADPKD mouse models with severe cystic kidney disease phenotypes.GT dramatically inhibited renal cyst development,decreased ADPKD mouse kidney volume and the cyst index inside proving GT cyst inhibition in vivo.By Western blot,we proved GT down-regulated Ras/MAPK signal pathway without detectable effect on mTOR signal pathway both in MDCK cells and two ADPKD mouse kidneys.CONCLUSIONGT retard renal cyst development both in vitro and in vivo significantly.The related mechanisms were involved in GT promoting renal tubular epithelial cell differentiation,down-regulating intracellular cAMP level and Ras/MAPK signal pathway.

polycystic kidney disease;Ganoderma triterpenes;mTOR signal pathway

The project supported by National Natural Science Foundation of China(81261160507,81330074,81620108029 and 81170632);and Beijing Natural Science Foundation(7172113)

Bao-xue YANG,Tel:(010)82805622,E-mail:baoxue@bjmu.edu.cn