PMID- 21345977
OWN - NLM
STAT- MEDLINE
DCOM- 20110701
LR  - 20211203
IS  - 1522-1466 (Electronic)
IS  - 1522-1466 (Linking)
VI  - 300
IP  - 5
DP  - 2011 May
TI  - Curcumin inhibits cystogenesis by simultaneous interference of multiple signaling 
      pathways: in vivo evidence from a Pkd1-deletion model.
PG  - F1193-202
LID - 10.1152/ajprenal.00419.2010 [doi]
AB  - 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.
FAU - Leonhard, Wouter N
AU  - Leonhard WN
AD  - Department of Human Genetics, Leiden Univ. Medical Center, The Netherlands.
FAU - van der Wal, Annemieke
AU  - van der Wal A
FAU - Novalic, Zlata
AU  - Novalic Z
FAU - Kunnen, Steven J
AU  - Kunnen SJ
FAU - Gansevoort, Ron T
AU  - Gansevoort RT
FAU - Breuning, Martijn H
AU  - Breuning MH
FAU - de Heer, Emile
AU  - de Heer E
FAU - Peters, Dorien J M
AU  - Peters DJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110223
PL  - United States
TA  - Am J Physiol Renal Physiol
JT  - American journal of physiology. Renal physiology
JID - 100901990
RN  - 0 (Ribosomal Protein S6)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (Stat3 protein, mouse)
RN  - 0 (TRPP Cation Channels)
RN  - 0 (polycystic kidney disease 1 protein)
RN  - 0 (ribosomal protein S6, mouse)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - IT942ZTH98 (Curcumin)
SB  - IM
MH  - Animals
MH  - Cell Proliferation/drug effects
MH  - Cells, Cultured
MH  - Curcumin/*pharmacology
MH  - Cytoprotection
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Kidney/*drug effects/enzymology/pathology
MH  - Mice
MH  - Mice, Knockout
MH  - Organ Size/drug effects
MH  - Phosphorylation
MH  - Polycystic Kidney, Autosomal Dominant/enzymology/genetics/pathology/*prevention & 
      control
MH  - Renal Insufficiency/enzymology/genetics/pathology/*prevention & control
MH  - Ribosomal Protein S6/metabolism
MH  - STAT3 Transcription Factor/metabolism
MH  - Signal Transduction/*drug effects
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - TRPP Cation Channels/*deficiency/genetics
EDAT- 2011/02/25 06:00
MHDA- 2011/07/02 06:00
CRDT- 2011/02/25 06:00
PHST- 2011/02/25 06:00 [entrez]
PHST- 2011/02/25 06:00 [pubmed]
PHST- 2011/07/02 06:00 [medline]
AID - ajprenal.00419.2010 [pii]
AID - 10.1152/ajprenal.00419.2010 [doi]
PST - ppublish
SO  - Am J Physiol Renal Physiol. 2011 May;300(5):F1193-202. doi: 
      10.1152/ajprenal.00419.2010. Epub 2011 Feb 23.