PMID- 24193408
OWN - NLM
STAT- MEDLINE
DCOM- 20150223
LR  - 20211203
IS  - 1432-2013 (Electronic)
IS  - 0031-6768 (Linking)
VI  - 466
IP  - 8
DP  - 2014 Aug
TI  - Polycystin-1 but not polycystin-2 deficiency causes upregulation of the mTOR 
      pathway and can be synergistically targeted with rapamycin and metformin.
PG  - 1591-604
LID - 10.1007/s00424-013-1394-x [doi]
AB  - Autosomal dominant polycystic kidney disease (ADPKD) is caused by 
      loss-of-function mutations in either PKD1 or PKD2 genes, which encode 
      polycystin-1 (TRPP1) and polycystin-2 (TRPP2), respectively. Increased activity 
      of the mammalian target of rapamycin (mTOR) pathway has been shown in PKD1 
      mutants but is less documented for PKD2 mutants. Clinical trials using mTOR 
      inhibitors were disappointing, while the AMP-activated kinase (AMPK) activator, 
      metformin is not yet tested in patients. Here, we studied the mTOR activity and 
      its upstream pathways in several human and mouse renal cell models with either 
      siRNA or stable knockdown and with overexpression of TRPP2. Our data reveal for 
      the first time differences between TRPP1 and TRPP2 deficiency. In contrast to 
      TRPP1 deficiency, TRPP2-deficient cells did neither display excessive activation 
      of the mTOR-kinase complex nor inhibition of AMPK activity, while ERK1/2 and Akt 
      activity were similarly affected among TRPP1- and TRPP2-deficient cells. 
      Furthermore, cell proliferation was more pronounced in TRPP1 than in 
      TRPP2-deficient cells. Interestingly, combining low concentrations of rapamycin 
      and metformin was more effective for inhibiting mTOR complex 1 activity in 
      TRPP1-deficient cells than either drug alone. Our results demonstrate a 
      synergistic effect of a combination of low concentrations of drugs suppressing 
      the increased mTOR activity in TRPP1-deficient cells. This novel insight can be 
      exploited in future clinical trials to optimize the efficiency and avoiding side 
      effects of drugs in the treatment of ADPKD patients with PKD1 mutations. 
      Furthermore, as TRPP2 deficiency by itself did not affect mTOR signaling, this 
      may underlie the differences in phenotype, and genetic testing has to be 
      considered for selecting patients for the ongoing trials.
FAU - Mekahli, Djalila
AU  - Mekahli D
AD  - Laboratory of Molecular and Cellular Signaling, Department of Cellular and 
      Molecular Medicine, KU Leuven, Campus Gasthuisberg O&N I, Leuven, Belgium, 
      Djalila.mekahli@uzleuven.be.
FAU - Decuypere, Jean-Paul
AU  - Decuypere JP
FAU - Sammels, Eva
AU  - Sammels E
FAU - Welkenhuyzen, Kirsten
AU  - Welkenhuyzen K
FAU - Schoeber, Joost
AU  - Schoeber J
FAU - Audrezet, Marie-Pierre
AU  - Audrezet MP
FAU - Corvelyn, Anniek
AU  - Corvelyn A
FAU - Dechenes, Georges
AU  - Dechenes G
FAU - Ong, Albert C M
AU  - Ong AC
FAU - Wilmer, Martijn J
AU  - Wilmer MJ
FAU - van den Heuvel, Lambertus
AU  - van den Heuvel L
FAU - Bultynck, Geert
AU  - Bultynck G
FAU - Parys, Jan B
AU  - Parys JB
FAU - Missiaen, Ludwig
AU  - Missiaen L
FAU - Levtchenko, Elena
AU  - Levtchenko E
FAU - De Smedt, Humbert
AU  - De Smedt H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131106
PL  - Germany
TA  - Pflugers Arch
JT  - Pflugers Archiv : European journal of physiology
JID - 0154720
RN  - 0 (TRPP Cation Channels)
RN  - 0 (polycystic kidney disease 1 protein)
RN  - 0 (polycystic kidney disease 2 protein)
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Drug Synergism
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Metformin/*pharmacology
MH  - Mice
MH  - Mutation
MH  - Polycystic Kidney, Autosomal Dominant/genetics/metabolism
MH  - Signal Transduction/*drug effects
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - TRPP Cation Channels/*deficiency/genetics
MH  - Up-Regulation
EDAT- 2013/11/07 06:00
MHDA- 2015/02/24 06:00
CRDT- 2013/11/07 06:00
PHST- 2013/05/17 00:00 [received]
PHST- 2013/10/21 00:00 [accepted]
PHST- 2013/09/30 00:00 [revised]
PHST- 2013/11/07 06:00 [entrez]
PHST- 2013/11/07 06:00 [pubmed]
PHST- 2015/02/24 06:00 [medline]
AID - 10.1007/s00424-013-1394-x [doi]
PST - ppublish
SO  - Pflugers Arch. 2014 Aug;466(8):1591-604. doi: 10.1007/s00424-013-1394-x. Epub 
      2013 Nov 6.