PMID- 21262823
OWN - NLM
STAT- MEDLINE
DCOM- 20110330
LR  - 20220316
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 108
IP  - 6
DP  - 2011 Feb 8
TI  - Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis.
PG  - 2462-7
LID - 10.1073/pnas.1011498108 [doi]
AB  - Renal cyst development and expansion in autosomal dominant polycystic kidney 
      disease (ADPKD) involves both fluid secretion and abnormal proliferation of 
      cyst-lining epithelial cells. The chloride channel of the cystic fibrosis 
      transmembrane conductance regulator (CFTR) participates in secretion of cyst 
      fluid, and the mammalian target of rapamycin (mTOR) pathway may drive 
      proliferation of cyst epithelial cells. CFTR and mTOR are both negatively 
      regulated by AMP-activated protein kinase (AMPK). Metformin, a drug in wide 
      clinical use, is a pharmacological activator of AMPK. We find that metformin 
      stimulates AMPK, resulting in inhibition of both CFTR and the mTOR pathways. 
      Metformin induces significant arrest of cystic growth in both in vitro and ex 
      vivo models of renal cystogenesis. In addition, metformin administration produces 
      a significant decrease in the cystic index in two mouse models of ADPKD. Our 
      results suggest a possible role for AMPK activation in slowing renal cystogenesis 
      as well as the potential for therapeutic application of metformin in the context 
      of ADPKD.
FAU - Takiar, Vinita
AU  - Takiar V
AD  - Department of Cellular and Molecular Physiology, Yale School of Medicine, New 
      Haven, CT 06520, USA.
FAU - Nishio, Saori
AU  - Nishio S
FAU - Seo-Mayer, Patricia
AU  - Seo-Mayer P
FAU - King, J Darwin Jr
AU  - King JD Jr
FAU - Li, Hui
AU  - Li H
FAU - Zhang, Li
AU  - Zhang L
FAU - Karihaloo, Anil
AU  - Karihaloo A
FAU - Hallows, Kenneth R
AU  - Hallows KR
FAU - Somlo, Stefan
AU  - Somlo S
FAU - Caplan, Michael J
AU  - Caplan MJ
LA  - eng
GR  - CDMRP PR093488/PR/OCPHP CDC HHS/United States
GR  - F30DK083221/DK/NIDDK NIH HHS/United States
GR  - R01 DK075048-03/DK/NIDDK NIH HHS/United States
GR  - R01 DK054053/DK/NIDDK NIH HHS/United States
GR  - DK57328/DK/NIDDK NIH HHS/United States
GR  - DK51041/DK/NIDDK NIH HHS/United States
GR  - R01 DK075048/DK/NIDDK NIH HHS/United States
GR  - DK17433/DK/NIDDK NIH HHS/United States
GR  - F30 DK083221/DK/NIDDK NIH HHS/United States
GR  - T32HL007563/HL/NHLBI NIH HHS/United States
GR  - T32 GM007205/GM/NIGMS NIH HHS/United States
GR  - MSTP TG 5T32GM07205/GM/NIGMS NIH HHS/United States
GR  - DK075048/DK/NIDDK NIH HHS/United States
GR  - P01 DK017433/DK/NIDDK NIH HHS/United States
GR  - R01 DK075048-02/DK/NIDDK NIH HHS/United States
GR  - P50 DK057328/DK/NIDDK NIH HHS/United States
GR  - R01 DK051041/DK/NIDDK NIH HHS/United States
GR  - DK54053/DK/NIDDK NIH HHS/United States
GR  - R01 DK075048-04/DK/NIDDK NIH HHS/United States
GR  - R01 DK075048-05/DK/NIDDK NIH HHS/United States
GR  - T32 HL007563/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110124
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Hypoglycemic Agents)
RN  - 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator)
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinases/genetics/*metabolism
MH  - Animals
MH  - Cell Line
MH  - *Cell Proliferation
MH  - Cystic Fibrosis Transmembrane Conductance Regulator/genetics/metabolism
MH  - Disease Models, Animal
MH  - Dogs
MH  - Epithelial Cells/*enzymology/pathology
MH  - Humans
MH  - Hypoglycemic Agents/pharmacology
MH  - Metformin/pharmacology
MH  - Mice
MH  - Mice, Transgenic
MH  - Polycystic Kidney, Autosomal Dominant/*enzymology/genetics/pathology
MH  - TOR Serine-Threonine Kinases/genetics/metabolism
PMC - PMC3038735
COIS- The authors declare no conflict of interest.
EDAT- 2011/01/26 06:00
MHDA- 2011/03/31 06:00
PMCR- 2011/08/08
CRDT- 2011/01/26 06:00
PHST- 2011/01/26 06:00 [entrez]
PHST- 2011/01/26 06:00 [pubmed]
PHST- 2011/03/31 06:00 [medline]
PHST- 2011/08/08 00:00 [pmc-release]
AID - 1011498108 [pii]
AID - 201011498 [pii]
AID - 10.1073/pnas.1011498108 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2011 Feb 8;108(6):2462-7. doi: 10.1073/pnas.1011498108. 
      Epub 2011 Jan 24.