title: Polycystin-1 but not polycystin-2 deficiency causes upregulation of the mTOR pathway and can be synergistically targeted with rapamycin and metformin.
abstract: 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.
authors.affiliation: 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.
authors.forename: Djalila
authors.initials: D
authors.lastname: Mekahli
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Decuypere
authors.forename: Eva
authors.initials: E
authors.lastname: Sammels
authors.forename: Kirsten
authors.initials: K
authors.lastname: Welkenhuyzen
authors.forename: Joost
authors.initials: J
authors.lastname: Schoeber
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Audrezet
authors.forename: Anniek
authors.initials: A
authors.lastname: Corvelyn
authors.forename: Georges
authors.initials: G
authors.lastname: Dechênes
authors.forename: Albert C M
authors.initials: AC
authors.lastname: Ong
authors.forename: Martijn J
authors.initials: MJ
authors.lastname: Wilmer
authors.forename: Lambertus
authors.initials: L
authors.lastname: van den Heuvel
authors.forename: Geert
authors.initials: G
authors.lastname: Bultynck
authors.forename: Jan B
authors.initials: JB
authors.lastname: Parys
authors.forename: Ludwig
authors.initials: L
authors.lastname: Missiaen
authors.forename: Elena
authors.initials: E
authors.lastname: Levtchenko
authors.forename: Humbert
authors.initials: H
authors.lastname: De Smedt
mesh_terms: D000818:Animals; D004357:Drug Synergism; D055785:Gene Knockdown Techniques; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D009154:Mutation; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D050396:TRPP Cation Channels / Q000172:deficiency* / Q000235:genetics; D015854:Up-Regulation
chemical_list: D008687:Metformin; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D050396:TRPP Cation Channels