title: Curcumin inhibits cystogenesis by simultaneous interference of multiple signaling pathways: in vivo evidence from a Pkd1-deletion model.
abstract: Autosomal dominant polycystic kidney disease (ADPKD) caused by mutations in either the PKD1 or PKD2 gene is a major cause of end-stage renal failure. A number of compounds targeting specific signaling pathways were able to inhibit cystogenesis in rodent models and are currently being tested in clinical trials. However, given the complex signaling in ADPKD, an ideal therapy would likely have to comprise several pathways at once. Therefore, multitarget compounds may provide promising therapeutic interventions for the treatment of ADPKD. To test this hypothesis, we treated Pkd1-deletion mice with diferuloylmethane (curcumin), a compound without appreciable side effects and known to modulate several pathways that are also altered in ADPKD, e.g., mammalian target of rapamycin (mTOR) and Wnt signaling. After conditional inactivation of Pkd1, mTOR signaling was indeed elevated in cystic kidneys. Interestingly, also activation of signal transducers and activator of transcription 3 (STAT3) strongly correlated with cyst progression. Both pathways were effectively inhibited in vitro by curcumin. Importantly, Pkd1-deletion mice that were treated with curcumin and killed at an early stage of PKD displayed improved renal histology and reduced STAT3 activation, proliferation index, cystic index, and kidney weight/body weight ratios. In addition, renal failure was significantly postponed in mice with severe PKD. These data suggest that multitarget compounds hold promising potential for safe and effective treatment of ADPKD.
authors.affiliation: Department of Human Genetics, Leiden Univ. Medical Center, The Netherlands.
authors.forename: Wouter N
authors.initials: WN
authors.lastname: Leonhard
authors.forename: Annemieke
authors.initials: A
authors.lastname: van der Wal
authors.forename: Zlata
authors.initials: Z
authors.lastname: Novalic
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Kunnen
authors.forename: Ron T
authors.initials: RT
authors.lastname: Gansevoort
authors.forename: Martijn H
authors.initials: MH
authors.lastname: Breuning
authors.forename: Emile
authors.initials: E
authors.lastname: de Heer
authors.forename: Dorien J M
authors.initials: DJ
authors.lastname: Peters
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003474:Curcumin / Q000494:pharmacology*; D019610:Cytoprotection; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D010766:Phosphorylation; D016891:Polycystic Kidney, Autosomal Dominant / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D051437:Renal Insufficiency / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D038601:Ribosomal Protein S6 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D050396:TRPP Cation Channels / Q000172:deficiency* / Q000235:genetics
chemical_list: D003474:Curcumin; D038601:Ribosomal Protein S6; D050796:STAT3 Transcription Factor; D058570:TOR Serine-Threonine Kinases; D050396:TRPP Cation Channels; C494087:Stat3 protein, mouse; C448579:ribosomal protein S6, mouse; C546843:mTOR protein, mouse