PMID- 23022334
OWN - NLM
STAT- MEDLINE
DCOM- 20130417
LR  - 20211203
IS  - 1879-0712 (Electronic)
IS  - 0014-2999 (Linking)
VI  - 696
IP  - 1-3
DP  - 2012 Dec 5
TI  - Involvement of autophagy in the pharmacological effects of the mTOR inhibitor 
      everolimus in acute kidney injury.
PG  - 143-54
LID - S0014-2999(12)00764-9 [pii]
LID - 10.1016/j.ejphar.2012.09.010 [doi]
AB  - Inhibitors of mammalian target of rapamycin (mTOR) have immunosuppressive and 
      anti-cancer effects, but their effects on the progression of kidney disease are 
      not fully understood. Using cells from normal kidney epithelial cell lines, we 
      found that the antiproliferative effects of mTOR inhibitor everolimus accompanied 
      the accumulation of a marker for cellular autophagic activity, the 
      phosphatidylethanolamine-conjugated form of microtubule-associated protein 1 
      light chain 3 (LC3-II) in cells. We also showed that the primary autophagy factor 
      UNC-51-like kinase 1 was involved in the antiproliferative effects of everolimus. 
      Levels of LC3-II decreased in the kidneys of rats treated with 
      ischemia-reperfusion or cisplatin; however, renal LC3-II levels increased after 
      administration of everolimus to rats subjected to ischemia-reperfusion or 
      cisplatin treatment. Simultaneously, increased signals for kidney injury 
      molecule-1 and single-stranded DNA and decreased signals for Ki-67 in the 
      proximal tubules were observed after treatment with everolimus, indicating that 
      everolimus diminished renal function after acute tubular injury. We also found 
      leakage of LC3 protein into rat urine after treatment with everolimus, and 
      urinary LC3 protein was successfully measured between 0.1 and 500ng/mL by using 
      an enzyme-linked immunosorbent assay. Urinary LC3 levels were increased after 
      administration of everolimus to rats subjected to ischemia-reperfusion or 
      cisplatin treatment, suggesting that renal LC3-II and urinary LC3 protein are new 
      biomarkers for autophagy in acute kidney injury. Taken together, our results 
      demonstrated that the induction of autophagy by everolimus aggravates tubular 
      dysfunction during recovery from kidney injury.
CI  - Copyright (c) 2012 Elsevier B.V. All rights reserved.
FAU - Nakagawa, Shunsaku
AU  - Nakagawa S
AD  - Department of Pharmacy, Kyoto University Hospital, Kyoto 606-8507, Japan.
FAU - Nishihara, Kumiko
AU  - Nishihara K
FAU - Inui, Ken-ichi
AU  - Inui K
FAU - Masuda, Satohiro
AU  - Masuda S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120926
PL  - Netherlands
TA  - Eur J Pharmacol
JT  - European journal of pharmacology
JID - 1254354
RN  - 0 (Biomarkers)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (LC3 protein, rat)
RN  - 0 (Microtubule-Associated Proteins)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Acute Kidney Injury/*metabolism
MH  - Animals
MH  - Autophagy/*physiology
MH  - Biomarkers/metabolism
MH  - Cell Line
MH  - Dogs
MH  - Everolimus
MH  - Humans
MH  - Immunosuppressive Agents/*pharmacology
MH  - Kidney/metabolism
MH  - Microtubule-Associated Proteins/metabolism
MH  - Muscle, Skeletal/metabolism
MH  - Rats
MH  - Rats, Wistar
MH  - Sirolimus/*analogs & derivatives/pharmacology
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors
EDAT- 2012/10/02 06:00
MHDA- 2013/04/18 06:00
CRDT- 2012/10/02 06:00
PHST- 2012/04/27 00:00 [received]
PHST- 2012/09/05 00:00 [revised]
PHST- 2012/09/17 00:00 [accepted]
PHST- 2012/10/02 06:00 [entrez]
PHST- 2012/10/02 06:00 [pubmed]
PHST- 2013/04/18 06:00 [medline]
AID - S0014-2999(12)00764-9 [pii]
AID - 10.1016/j.ejphar.2012.09.010 [doi]
PST - ppublish
SO  - Eur J Pharmacol. 2012 Dec 5;696(1-3):143-54. doi: 10.1016/j.ejphar.2012.09.010. 
      Epub 2012 Sep 26.