PMID- 28706237
OWN - NLM
STAT- MEDLINE
DCOM- 20190116
LR  - 20220409
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 7
IP  - 1
DP  - 2017 Jul 13
TI  - Suppressed autophagic response underlies augmentation of renal 
      ischemia/reperfusion injury by type 2 diabetes.
PG  - 5311
LID - 10.1038/s41598-017-05667-5 [doi]
LID - 5311
AB  - Diabetes mellitus is a major risk factor for acute kidney injury (AKI). Here, we 
      hypothesized that suppression of autophagic response underlies aggravation of 
      renal ischemia/reperfusion (I/R) injury by type 2 diabetes mellitus (T2DM). In 
      OLETF, a rat model of T2DM, and its non-diabetic control, LETO, AKI was induced 
      by unilateral nephrectomy and 30-min occlusion and 24-h reperfusion of the renal 
      artery in the contralateral kidney. Levels of serum creatinine and blood urea 
      nitrogen and tubular injury score after I/R were significantly higher in OLETF 
      than in LETO. Administration of chloroquine, a widely used autophagy inhibitor, 
      aggravated I/R-induced renal injury in LETO, but not in OLETF. In contrast to 
      LETO, OLETF exhibited no increase in autophagosomes in the proximal tubules after 
      I/R. Immunoblotting showed that I/R activated the AMPK/ULK1 pathway in LETO but 
      not in OLETF, and mTORC1 activation after I/R was enhanced in OLETF. Treatment of 
      OLETF with rapamycin, an mTORC1 inhibitor, partially restored autophagic 
      activation in response to I/R and significantly attenuated I/R-induced renal 
      injury. Collectively, these findings indicate that suppressed autophagic 
      activation in proximal tubules by impaired AMPK/ULK1 signaling and upregulated 
      mTORC1 activation underlies T2DM-induced worsening of renal I/R injury.
FAU - Muratsubaki, Shingo
AU  - Muratsubaki S
AD  - Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical 
      University School of Medicine, Sapporo, Japan.
FAU - Kuno, Atsushi
AU  - Kuno A
AD  - Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical 
      University School of Medicine, Sapporo, Japan.
AD  - Department of Pharmacology, Sapporo Medical University School of Medicine, 
      Sapporo, Japan.
FAU - Tanno, Masaya
AU  - Tanno M
AD  - Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical 
      University School of Medicine, Sapporo, Japan.
FAU - Miki, Takayuki
AU  - Miki T
AD  - Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical 
      University School of Medicine, Sapporo, Japan.
FAU - Yano, Toshiyuki
AU  - Yano T
AD  - Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical 
      University School of Medicine, Sapporo, Japan.
FAU - Sugawara, Hirohito
AU  - Sugawara H
AD  - Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical 
      University School of Medicine, Sapporo, Japan.
FAU - Shibata, Satoru
AU  - Shibata S
AD  - Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical 
      University School of Medicine, Sapporo, Japan.
FAU - Abe, Koki
AU  - Abe K
AD  - Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical 
      University School of Medicine, Sapporo, Japan.
FAU - Ishikawa, Satoko
AU  - Ishikawa S
AD  - Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical 
      University School of Medicine, Sapporo, Japan.
FAU - Ohno, Kouhei
AU  - Ohno K
AD  - Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical 
      University School of Medicine, Sapporo, Japan.
FAU - Kimura, Yukishige
AU  - Kimura Y
AD  - Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical 
      University School of Medicine, Sapporo, Japan.
FAU - Tatekoshi, Yuki
AU  - Tatekoshi Y
AD  - Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical 
      University School of Medicine, Sapporo, Japan.
FAU - Nakata, Kei
AU  - Nakata K
AD  - Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical 
      University School of Medicine, Sapporo, Japan.
FAU - Ohwada, Wataru
AU  - Ohwada W
AD  - Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical 
      University School of Medicine, Sapporo, Japan.
FAU - Mizuno, Masashi
AU  - Mizuno M
AD  - Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical 
      University School of Medicine, Sapporo, Japan.
FAU - Miura, Tetsuji
AU  - Miura T
AD  - Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical 
      University School of Medicine, Sapporo, Japan. miura@sapmed.ac.jp.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170713
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - AYI8EX34EU (Creatinine)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
SB  - IM
MH  - Animals
MH  - *Autophagy
MH  - Blood Urea Nitrogen
MH  - Creatinine/blood
MH  - Diabetes Mellitus, Type 2/*complications/*pathology
MH  - Disease Models, Animal
MH  - Kidney Diseases/pathology/*physiopathology
MH  - Kidney Tubules, Proximal/pathology
MH  - Mechanistic Target of Rapamycin Complex 1/analysis
MH  - Rats
MH  - Reperfusion Injury/pathology/*physiopathology
PMC - PMC5509657
COIS- The authors declare that they have no competing interests.
EDAT- 2017/07/15 06:00
MHDA- 2019/01/17 06:00
PMCR- 2017/07/13
CRDT- 2017/07/15 06:00
PHST- 2017/01/31 00:00 [received]
PHST- 2017/06/01 00:00 [accepted]
PHST- 2017/07/15 06:00 [entrez]
PHST- 2017/07/15 06:00 [pubmed]
PHST- 2019/01/17 06:00 [medline]
PHST- 2017/07/13 00:00 [pmc-release]
AID - 10.1038/s41598-017-05667-5 [pii]
AID - 5667 [pii]
AID - 10.1038/s41598-017-05667-5 [doi]
PST - epublish
SO  - Sci Rep. 2017 Jul 13;7(1):5311. doi: 10.1038/s41598-017-05667-5.