PMID- 31042058
OWN - NLM
STAT- MEDLINE
DCOM- 20200316
LR  - 20211204
IS  - 1522-1466 (Electronic)
IS  - 1931-857X (Print)
IS  - 1522-1466 (Linking)
VI  - 317
IP  - 1
DP  - 2019 Jul 1
TI  - A study of sirolimus and mTOR kinase inhibitor in a hypomorphic Pkd1 mouse model 
      of autosomal dominant polycystic kidney disease.
PG  - F187-F196
LID - 10.1152/ajprenal.00051.2019 [doi]
AB  - Autosomal dominant polycystic kidney disease (PKD) is characterized by cyst 
      formation and growth, which are partially driven by abnormal proliferation of 
      tubular cells. Proproliferative mechanistic target of rapamycin (mTOR) complexes 
      1 and 2 (mTORC1 and mTORC2) are activated in the kidneys of mice with PKD. 
      Sirolimus indirectly inhibits mTORC1. Novel mTOR kinase inhibitors directly 
      inhibit mTOR kinase, resulting in the inhibition of mTORC1 and mTORC2. The aim of 
      the present study was to determine the effects of sirolimus versus the mTOR 
      kinase inhibitor torin2 on cyst growth and kidney function in the Pkd1 p.R3277C 
      (Pkd1(RC/RC)) mouse model, a hypomorphic Pkd1 model orthologous to the human 
      condition, and to determine the effects of sirolimus versus torin2 on mTORC1 and 
      mTORC2 signaling in PKD1(-/-) cells and in the kidneys of Pkd1(RC/RC) mice. In 
      vitro, both inhibitors reduced mTORC1 and mTORC2 phosphorylated substrates and 
      negatively impacted cellular metabolic activity, as measured by MTT assay. 
      Pkd1(RC/RC) mice were treated with sirolimus or torin2 from 50 to 120 days of 
      age. Torin2 was as effective as sirolimus in decreasing cyst growth and improving 
      loss of kidney function. Both sirolimus and torin2 decreased phosphorylated S6 
      protein, phosphorylated eukaryotic translation initiation factor 4E-binding 
      protein 1, phosphorylated Akt, and proliferation in Pkd1(RC/RC) kidneys. In 
      conclusion, torin2 and sirolimus were equally effective in decreasing cyst burden 
      and improving kidney function and mediated comparable effects on mTORC1 and 
      mTORC2 signaling and proliferation in the Pkd1(RC/RC) kidney.
FAU - Holditch, Sara J
AU  - Holditch SJ
AD  - Division of Renal Diseases and Hypertension, University of Colorado at Denver , 
      Aurora, Colorado.
FAU - Brown, Carolyn N
AU  - Brown CN
AD  - Division of Renal Diseases and Hypertension, University of Colorado at Denver , 
      Aurora, Colorado.
FAU - Atwood, Daniel J
AU  - Atwood DJ
AD  - Division of Renal Diseases and Hypertension, University of Colorado at Denver , 
      Aurora, Colorado.
FAU - Lombardi, Andrew M
AU  - Lombardi AM
AD  - Division of Renal Diseases and Hypertension, University of Colorado at Denver , 
      Aurora, Colorado.
FAU - Nguyen, Khoa N
AU  - Nguyen KN
AD  - Division of Renal Diseases and Hypertension, University of Colorado at Denver , 
      Aurora, Colorado.
FAU - Toll, Harrison W
AU  - Toll HW
AD  - Division of Renal Diseases and Hypertension, University of Colorado at Denver , 
      Aurora, Colorado.
FAU - Hopp, Katharina
AU  - Hopp K
AD  - Division of Renal Diseases and Hypertension, University of Colorado at Denver , 
      Aurora, Colorado.
FAU - Edelstein, Charles L
AU  - Edelstein CL
AD  - Division of Renal Diseases and Hypertension, University of Colorado at Denver , 
      Aurora, Colorado.
LA  - eng
GR  - I01 BX003803/BX/BLRD VA/United States
GR  - T32 GM007635/GM/NIGMS NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20190501
PL  - United States
TA  - Am J Physiol Renal Physiol
JT  - American journal of physiology. Renal physiology
JID - 100901990
RN  - 0 
      (9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo(h)(1,6)naphthyridin-2(1H)-one)
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (EIF4EBP1 protein, human)
RN  - 0 (Naphthyridines)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (TRPP Cation Channels)
RN  - 0 (polycystic kidney disease 1 protein)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/metabolism
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Cell Cycle Proteins/metabolism
MH  - Cell Proliferation/drug effects
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - Kidney Tubules/*drug effects/enzymology/physiopathology
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Mice, Mutant Strains
MH  - *Mutation
MH  - Naphthyridines/*pharmacology
MH  - Phosphorylation
MH  - Polycystic Kidney, Autosomal Dominant/*drug 
      therapy/enzymology/genetics/physiopathology
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Ribosomal Protein S6 Kinases/metabolism
MH  - Signal Transduction
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
MH  - TRPP Cation Channels/*genetics
PMC - PMC7717114
OTO - NOTNLM
OT  - apoptosis
OT  - autosomal dominant polycystic kidney disease
OT  - polycystic
OT  - proliferation
OT  - sirolimus
OT  - torin2
COIS- C. L. Edelstein is on the Data Safety Monitoring Board for Conatus 
      Pharmaceuticals.
EDAT- 2019/05/02 06:00
MHDA- 2020/03/17 06:00
PMCR- 2020/07/01
CRDT- 2019/05/02 06:00
PHST- 2019/05/02 06:00 [pubmed]
PHST- 2020/03/17 06:00 [medline]
PHST- 2019/05/02 06:00 [entrez]
PHST- 2020/07/01 00:00 [pmc-release]
AID - F-00051-2019 [pii]
AID - 10.1152/ajprenal.00051.2019 [doi]
PST - ppublish
SO  - Am J Physiol Renal Physiol. 2019 Jul 1;317(1):F187-F196. doi: 
      10.1152/ajprenal.00051.2019. Epub 2019 May 1.