Suppressed autophagic response underlies augmentation of renal ischemia/reperfusion injury by type 2 diabetes

Muratsubaki, Shingo; Kuno, Atsushi; Tanno, Masaya; Miki, Takayuki; Yano, Toshiyuki; Sugawara, Hirohito; Shibata, Satoru; Abe, Koki; Ishikawa, Satoko; Ohno, Kouhei; Kimura, Yoshinobu; Tatekoshi, Yuki; Nakata, Kei; Ohwada, Wataru; Mizuno, Masashi; Miura, Tetsuji

doi:10.1038/s41598-017-05667-5

Cited by 29 publications

(25 citation statements)

References 67 publications

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“…4C). Although our previous studies showed that impaired activation of an AMP-activated protein kinase (AMPK) and hyperactivation of mTORC1 are involved in suppressed autophagy in OLETF (Murase et al 2015;Muratsubaki et al 2017), we could not detect significant effects of empagliflozin on AMPK or mTORC1 in OLETF in the noninfarcted myocardium (Oshima et al, unpubl. observation).…”

Section: Discussionmentioning

confidence: 66%

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Empagliflozin normalizes the size and number of mitochondria and prevents reduction in mitochondrial size after myocardial infarction in diabetic hearts

et al. 2018

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To explore mechanisms by which SGLT2 inhibitors protect diabetic hearts from heart failure, we examined the effect of empagliflozin (Empa) on the ultrastructure of cardiomyocytes in the noninfarcted region of the diabetic heart after myocardial infarction (MI). OLETF, a rat model of type 2 diabetes, and its nondiabetic control, LETO, received a sham operation or left coronary artery ligation 12 h before tissue sampling. Tissues were sampled from the posterior ventricle (i.e., the remote noninfarcted region in rats with MI). The number of mitochondria was larger and small mitochondria were more prevalent in OLETF than in LETO. Fis1 expression level was higher in OLETF than in LETO, while phospho‐Ser637‐Drp1, total Drp1, Mfn1/2, and OPA1 levels were comparable. MI further reduced the size of mitochondria with increased Drp1‐Ser616 phosphorylation in OLETF. The number of autophagic vacuoles was unchanged after MI in LETO but was decreased in OLETF. Lipid droplets in cardiomyocytes and tissue triglycerides were increased in OLETF. Empa administration (10 mg/kg per day) reduced blood glucose and triglycerides and paradoxically increased lipid droplets in cardiomyocytes in OLETF. Empa suppressed Fis1 upregulation, increased Bnip3 expression, and prevented reduction in both mitochondrial size and autophagic vacuole number after MI in OLETF. Together with the results of our parallel study showing upregulation of SOD2 and catalase by Empa, the results indicate that Empa normalizes the size and number of mitochondria in diabetic hearts and that diabetes‐induced excessive reduction in mitochondrial size after MI was prevented by Empa via suppression of ROS and restoration of autophagy.

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Section: Discussionmentioning

confidence: 66%

“…; Muratsubaki et al. ), we could not detect significant effects of empagliflozin on AMPK or mTORC1 in OLETF in the noninfarcted myocardium (Oshima et al., unpubl. observation).…”

Section: Discussionmentioning

confidence: 76%

Empagliflozin normalizes the size and number of mitochondria and prevents reduction in mitochondrial size after myocardial infarction in diabetic hearts

et al. 2018

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“…As the correlation between blood βOHB and renal NGAL expression was modest ( r = −0.41), mechanisms other than increased βOHB are possibly involved in renoprotection by canagliflozin with pre‐MI fasting. Activation of AMPK is one of the candidates, but the present results showed that the contribution of AMPK to renoprotection against diabetes mellitus‐induced worsening of CRS was limited. It has been suggested that the reduction of oxygen consumption in the proximal tubules and prevention of cellular senescence are the mechanisms of renoprotection by an SGLT2 inhibitor, but whether these mechanisms are involved in amelioration of CRS should be examined in future studies.…”

Section: Discussionmentioning

confidence: 65%

“…First, OLETF spontaneously develop diabetes mellitus primarily by hyperphagia as a result of a lack of cholecystokinin-A receptor in the brain, and they show the typical phenotype of type 2 diabetes mellitus (i.e., obesity, hyperinsulinemia and hypertriglyceridemia) 19,20 . Second, OLETF at the ages of 25-30 weeks show an early stage of diabetic nephropathy: lower serum creatinine level with protein urea than that in Long-Evans Tokushima Otsuka rats (LETO), non-diabetes mellitus control rats 8,21,22 . Third, we previously found that renal susceptibility to type 1 CRS was higher in OLETF than in LETO 8 .…”

Section: Introductionmentioning

confidence: 98%

Canagliflozin, a sodium–glucose cotransporter 2 inhibitor, normalizes renal susceptibility to type 1 cardiorenal syndrome through reduction of renal oxidative stress in diabetic rats

Kimura

Kuno

Tanno

et al. 2019

J of Diabetes Invest

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Aims/Introduction Type 2 diabetes mellitus is a risk factor of acute kidney injury after myocardial infarction (MI), a form of cardiorenal syndrome. Recent clinical trials have shown that a sodium–glucose cotransporter 2 (SGLT2) inhibitor improved both cardiac and renal outcomes in patients with type 2 diabetes mellitus, but effects of an SGLT2 inhibitor on cardiorenal syndrome remain unclear. Materials and Methods Type 2 diabetes mellitus (Otsuka Long‐Evans Tokushima Fatty rats [OLETF]) and control (Long‐Evans Tokushima Otsuka rats [LETO]) were treated with canagliflozin, an SGLT2 inhibitor, for 2 weeks. Renal tissues were analyzed at 12 h after MI with or without preoperative fasting. Results Canagliflozin reduced blood glucose levels in OLETF, and blood β‐hydroxybutyrate levels were increased by canagliflozin only with fasting. MI increased neutrophil gelatinase‐associated lipocalin and kidney injury molecule‐1 protein levels in the kidney by 3.2‐ and 1.6‐fold, respectively, in OLETF, but not in LETO. The renal messenger ribonucleic acid level of Toll‐like receptor 4 was higher in OLETF than in LETO after MI, whereas messenger ribonucleic acid levels of cytokines/chemokines were not significantly different. Levels of lipid peroxides, nicotinamide adenine dinucleotide phosphate oxidase (NOX)2 and NOX4 proteins after MI were significantly higher in OLETF than in LETO. Canagliflozin with pre‐MI fasting suppressed MI‐induced renal expression of neutrophil gelatinase‐associated lipocalin and kidney injury molecule‐1 in OLETF, together with reductions in lipid peroxides and NOX proteins in the kidney. Blood β‐hydroxybutyrate levels before MI were inversely correlated with neutrophil gelatinase‐associated lipocalin protein levels in OLETF. Pre‐incubation with β‐hydroxybutyrate attenuated angiotensin II‐induced upregulation of NOX4 in NRK‐52E cells. Conclusions The findings suggest that SGLT2 inhibitor treatment with a fasting period protects kidneys from MI‐induced cardiorenal syndrome, possibly by β‐hydroxybutyrate‐mediated reduction of NOXs and oxidative stress, in type 2 diabetic rats.

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“…In these cells, viruses inhibit lysosomal degradation in the maturation step of autophagy and use autophagic membranes for the formation and release of the viral particles. 98 In type 2 diabetes, low micromolar CQ could inhibit autophagy and cause apoptosis of podocytes and exacerbate nephropathy. 93 In fact, basal autophagy has been proposed to play a pivotal role in sustaining mitochondrial function in lymphoma, and low CQ concentration may cause apoptosis in susceptible lymphoma cells.…”

Section: Cq Regulates Tissue Responses To Metabolic and Inflammatory mentioning

confidence: 99%

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

2019

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Chloroquines are 4-aminoquinoline-based drugs mainly used to treat malaria. At pharmacological concentrations, they have significant effects on tissue homeostasis, targeting diverse signaling pathways in mammalian cells. A key target pathway is autophagy, which regulates macromolecule turnover in the cell. In addition to affecting cellular metabolism and bioenergetic flow equilibrium, autophagy plays a pivotal role at the interface between inflammation and cancer progression. Chloroquines consequently have critical effects in tissue metabolic activity and importantly, in key functions of the immune system. In this article, we will review the work addressing the role of chloroquines in the homeostasis of mammalian tissue, and the potential strengths and weaknesses concerning their use in cancer therapy.

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Suppressed autophagic response underlies augmentation of renal ischemia/reperfusion injury by type 2 diabetes

Cited by 29 publications

References 67 publications

Empagliflozin normalizes the size and number of mitochondria and prevents reduction in mitochondrial size after myocardial infarction in diabetic hearts

Empagliflozin normalizes the size and number of mitochondria and prevents reduction in mitochondrial size after myocardial infarction in diabetic hearts

Canagliflozin, a sodium–glucose cotransporter 2 inhibitor, normalizes renal susceptibility to type 1 cardiorenal syndrome through reduction of renal oxidative stress in diabetic rats

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

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