Suppressed autophagic response underlies augmentation of renal ischemia/reperfusion injury by type 2 diabetes
Abstract 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 cont...
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doaj-63a54ac622c841ca87fa8f2d60c4ecd42020-12-08T02:58:51ZengNature Publishing GroupScientific Reports2045-23222017-07-017111310.1038/s41598-017-05667-5Suppressed autophagic response underlies augmentation of renal ischemia/reperfusion injury by type 2 diabetesShingo Muratsubaki0Atsushi Kuno1Masaya Tanno2Takayuki Miki3Toshiyuki Yano4Hirohito Sugawara5Satoru Shibata6Koki Abe7Satoko Ishikawa8Kouhei Ohno9Yukishige Kimura10Yuki Tatekoshi11Kei Nakata12Wataru Ohwada13Masashi Mizuno14Tetsuji Miura15Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of MedicineDepartment of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of MedicineDepartment of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of MedicineDepartment of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of MedicineDepartment of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of MedicineDepartment of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of MedicineDepartment of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of MedicineDepartment of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of MedicineDepartment of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of MedicineDepartment of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of MedicineDepartment of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of MedicineDepartment of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of MedicineDepartment of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of MedicineDepartment of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of MedicineDepartment of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of MedicineDepartment of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of MedicineAbstract 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.https://doi.org/10.1038/s41598-017-05667-5 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Shingo Muratsubaki Atsushi Kuno Masaya Tanno Takayuki Miki Toshiyuki Yano Hirohito Sugawara Satoru Shibata Koki Abe Satoko Ishikawa Kouhei Ohno Yukishige Kimura Yuki Tatekoshi Kei Nakata Wataru Ohwada Masashi Mizuno Tetsuji Miura |
spellingShingle |
Shingo Muratsubaki Atsushi Kuno Masaya Tanno Takayuki Miki Toshiyuki Yano Hirohito Sugawara Satoru Shibata Koki Abe Satoko Ishikawa Kouhei Ohno Yukishige Kimura Yuki Tatekoshi Kei Nakata Wataru Ohwada Masashi Mizuno Tetsuji Miura Suppressed autophagic response underlies augmentation of renal ischemia/reperfusion injury by type 2 diabetes Scientific Reports |
author_facet |
Shingo Muratsubaki Atsushi Kuno Masaya Tanno Takayuki Miki Toshiyuki Yano Hirohito Sugawara Satoru Shibata Koki Abe Satoko Ishikawa Kouhei Ohno Yukishige Kimura Yuki Tatekoshi Kei Nakata Wataru Ohwada Masashi Mizuno Tetsuji Miura |
author_sort |
Shingo Muratsubaki |
title |
Suppressed autophagic response underlies augmentation of renal ischemia/reperfusion injury by type 2 diabetes |
title_short |
Suppressed autophagic response underlies augmentation of renal ischemia/reperfusion injury by type 2 diabetes |
title_full |
Suppressed autophagic response underlies augmentation of renal ischemia/reperfusion injury by type 2 diabetes |
title_fullStr |
Suppressed autophagic response underlies augmentation of renal ischemia/reperfusion injury by type 2 diabetes |
title_full_unstemmed |
Suppressed autophagic response underlies augmentation of renal ischemia/reperfusion injury by type 2 diabetes |
title_sort |
suppressed autophagic response underlies augmentation of renal ischemia/reperfusion injury by type 2 diabetes |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2017-07-01 |
description |
Abstract 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. |
url |
https://doi.org/10.1038/s41598-017-05667-5 |
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