Background:Dysfunction or loss of podocytes causes proteinuria,which has been associated with both acute and chronic glomerular diseases.However,podocyte target treatments are still limited.Triptolide,a major active component of Tripterygium wilfordii Hook F,has dramatic antiproteinuric effect,but the mechanism is unclear.A transgenic zebrafish model of inducible podocyte injury has been established previously.In this transgenic zebrafish,the bacterial nitroreductase(NTR)is expressed specifically in podocytes under the control of zebrafish podocin promoter,the prodrug metronidazole(MTZ)can be converted into a cytotoxin only in podocytes,which leading to podocyte injury.Methods:We examined the effect of tripolide on transgenic zebrafish model of inducible podocyte injury.We treated zebrafish embryos with triptolide,then observed edema,measured proteinuria level as well as analyzed changes of podocin expression and foot process by immunostaining and Transmission Electron Microscope respectively.Furthermore,we performed an activated caspase-3 staining and applied microarray in tripolide-treated human podocyte.Finally,we validated the result of microarray by qRT-PCR in vitro and in vivo.Results:Triptolide effectively alleviated edema and proteinuria in zebrafish model.The antiproteinuric effect was associated with improvement of foot process effacement,restoration of podocin expression and distribution as well as inhibition of podocytes apoptosis.Comparison of the mRNA profile by microarray analysis showed GADD45 family expression was downregulated in triptolide treated human podocytes in vitro.GADD45B has been implicated in podocytes apoptosis.Triptolide could suppress the expression of GADD45 in both MTZ-treated zebrafish glomeruli and PAN-treated human podocytes.Conclusions:These results demonstrate that triptolide has direct effect on podocyte.Triptolide attenuates proteinuria and podocyte injury via reversing podocyte apoptosis and downregulation of gadd45 expression.