title: Triptolide is a traditional Chinese medicine-derived inhibitor of polycystic kidney disease.
abstract: During kidney organogenesis, tubular epithelial cells proliferate until a functional tubule is formed as sensed by cilia bending in response to fluid flow. This flow-induced ciliary mechanosensation opens the calcium (Ca(2+)) channel polycystin-2 (PC2), resulting in a calcium flux-mediated cell cycle arrest. Loss or mutation of either PC2 or its regulatory protein polycystin-1 (PC1) results in autosomal dominant polycystic kidney disease (ADPKD), characterized by cyst formation and growth and often leading to renal failure and death. Here we show that triptolide, the active diterpene in the traditional Chinese medicine Lei Gong Teng, induces Ca(2+) release by a PC2-dependent mechanism. Furthermore, in a murine model of ADPKD, triptolide arrests cellular proliferation and attenuates overall cyst formation by restoring Ca(2+) signaling in these cells. We anticipate that small molecule induction of PC2-dependent calcium release is likely to be a valid therapeutic strategy for ADPKD.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Leuenroth
authors.forename: Dayne
authors.initials: D
authors.lastname: Okuhara
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Shotwell
authors.forename: Glen S
authors.initials: GS
authors.lastname: Markowitz
authors.forename: Zhiheng
authors.initials: Z
authors.lastname: Yu
authors.forename: Stefan
authors.initials: S
authors.lastname: Somlo
authors.forename: Craig M
authors.initials: CM
authors.lastname: Crews
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D004847:Epithelial Cells / Q000166:cytology; D004852:Epoxy Compounds / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D008516:Medicine, Chinese Traditional; D051379:Mice; D008822:Mice, Transgenic; D010616:Phenanthrenes / Q000494:pharmacology*; D007690:Polycystic Kidney Diseases / Q000188:drug therapy*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D050396:TRPP Cation Channels / Q000378:metabolism*; D019076:Transgenes; D054462:p21-Activated Kinases
chemical_list: D002118:Calcium; D015220:Calcium Channels; D004224:Diterpenes; D004852:Epoxy Compounds; D007166:Immunosuppressive Agents; D010616:Phenanthrenes; D017346:Protein Serine-Threonine Kinases; D050396:TRPP Cation Channels; D054462:p21-Activated Kinases; C001899:triptolide