PMID- 30995114
OWN - NLM
STAT- MEDLINE
DCOM- 20200407
LR  - 20211204
IS  - 1522-1466 (Electronic)
IS  - 1522-1466 (Linking)
VI  - 317
IP  - 7
DP  - 2019 Jul 1
TI  - AMPK-mediated activation of Akt protects renal tubular cells from stress-induced 
      apoptosis in vitro and ameliorates ischemic AKI in vivo.
PG  - F1-F11
LID - 10.1152/ajprenal.00553.2018 [doi]
AB  - We have reported that preconditioning renal tubular cells (RTCs) with A-769662 [a 
      pharmacological activator of AMP-activated protein kinase (AMPK)] reduces 
      apoptosis of RTCs induced by subsequent stress and ameliorates the severity of 
      ischemic acute kidney injury (AKI) in mice. In the present study, we examined the 
      role of the phosphoinositide 3-kinase (PI3K)/Akt pathway in mediating these 
      effects. Using shRNA, we developed knockdown (KD) RTCs to confirm that any novel 
      effects of A-769662 are mediated specifically by AMPK. We reduced expression of 
      the total beta-domain of AMPK in KD RTCs by >80%. Control RTCs were transfected with 
      "scrambled" shRNA. Preconditioning control RTCs with A-769662 increased both the 
      phosphorylation (activity) of AMPK and survival of these cells when exposed to 
      subsequent stress, but neither effect was observed in KD cells. These data 
      demonstrate that activation of AMPK by A-769662 is profoundly impaired in KD 
      cells. A-769662 activated PI3K and Akt in control but not KD RTCs. These data 
      provide novel evidence that activation of the PI3K/Akt pathway by A-769662 is 
      mediated specifically through activation of AMPK and not by a nonspecific 
      mechanism. We also demonstrate that, in control RTCs, Akt plays a role in 
      mediating the antiapoptotic effects of A-769662. In addition, we provide evidence 
      that AMPK ameliorates the severity of ischemic AKI in mice and that this effect 
      is also partially mediated by Akt. Finally, we provide evidence that AMPK 
      activates PI3K by inhibiting mechanistic target of rapamycin complex 1 and 
      preventing mechanistic target of rapamycin complex 1-mediated inhibition of 
      insulin receptor substrate-1-associated activation of PI3K.
FAU - Lieberthal, Wilfred
AU  - Lieberthal W
AD  - Division of Nephrology, Department of Medicine, Stony Brook University Medical 
      Center , Stony Brook, New York.
AD  - Division of Nephrology, Department of Medicine, Northport Veterans Affairs 
      Hospital, Northport, New York.
FAU - Tang, Meiyi
AU  - Tang M
AD  - Division of Nephrology, Department of Medicine, Stony Brook University Medical 
      Center , Stony Brook, New York.
FAU - Abate, Mersema
AU  - Abate M
AD  - Division of Nephrology, Department of Medicine, Stony Brook University Medical 
      Center , Stony Brook, New York.
FAU - Lusco, Mark
AU  - Lusco M
AD  - Department of Pathology, Microbiology, and Immunology, Vanderbilt University 
      Medical Center , Nashville, Tennessee.
FAU - Levine, Jerrold S
AU  - Levine JS
AD  - Division of Nephrology, Department of Medicine, Jesse Brown Veterans Affairs 
      Hospital , Chicago, Illinois.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20190417
PL  - United States
TA  - Am J Physiol Renal Physiol
JT  - American journal of physiology. Renal physiology
JID - 100901990
RN  - 0 (Biphenyl Compounds)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Pyrones)
RN  - 0 (Thiophenes)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - P68477CD2C 
      (4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile)
SB  - IM
MH  - AMP-Activated Protein Kinases/genetics/*physiology
MH  - Acute Kidney Injury/etiology/pathology/*prevention & control
MH  - Animals
MH  - Apoptosis/drug effects/*physiology
MH  - Biphenyl Compounds
MH  - Cell Line
MH  - Enzyme Activation/drug effects
MH  - Gene Knockdown Techniques
MH  - Insulin Receptor Substrate Proteins/physiology
MH  - Ischemic Preconditioning
MH  - Kidney/blood supply
MH  - Kidney Tubules, Proximal/drug effects/*pathology
MH  - Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors
MH  - Mice
MH  - Phosphatidylinositol 3-Kinase/metabolism
MH  - Proto-Oncogene Proteins c-akt/*physiology
MH  - Pyrones/pharmacology
MH  - Reperfusion Injury/*complications
MH  - Thiophenes/pharmacology
OTO - NOTNLM
OT  - A-769662
OT  - AMP-activated protein kinase
OT  - Akt
OT  - acute kidney injury
OT  - phosphoinositide-3 kinase
EDAT- 2019/04/18 06:00
MHDA- 2020/04/09 06:00
CRDT- 2019/04/18 06:00
PHST- 2019/04/18 06:00 [pubmed]
PHST- 2020/04/09 06:00 [medline]
PHST- 2019/04/18 06:00 [entrez]
AID - 10.1152/ajprenal.00553.2018 [doi]
PST - ppublish
SO  - Am J Physiol Renal Physiol. 2019 Jul 1;317(7):F1-F11. doi: 
      10.1152/ajprenal.00553.2018. Epub 2019 Apr 17.