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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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/63a54ac622c841ca87fa8f2d60c4ecd4
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spelling	oai:doaj.org-article:63a54ac622c841ca87fa8f2d60c4ecd42021-12-02T12:32:45ZSuppressed autophagic response underlies augmentation of renal ischemia/reperfusion injury by type 2 diabetes10.1038/s41598-017-05667-52045-2322https://doaj.org/article/63a54ac622c841ca87fa8f2d60c4ecd42017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05667-5https://doaj.org/toc/2045-2322Abstract 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.Shingo MuratsubakiAtsushi KunoMasaya TannoTakayuki MikiToshiyuki YanoHirohito SugawaraSatoru ShibataKoki AbeSatoko IshikawaKouhei OhnoYukishige KimuraYuki TatekoshiKei NakataWataru OhwadaMasashi MizunoTetsuji MiuraNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
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
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 Portfolio
publishDate	2017
url	https://doaj.org/article/63a54ac622c841ca87fa8f2d60c4ecd4
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Suppressed autophagic response underlies augmentation of renal ischemia/reperfusion injury by type 2 diabetes

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