PMID- 30663266 OWN - NLM STAT- MEDLINE DCOM- 20200113 LR - 20231012 IS - 2040-1124 (Electronic) IS - 2040-1116 (Print) IS - 2040-1116 (Linking) VI - 10 IP - 4 DP - 2019 Jul TI - Canagliflozin, a sodium-glucose cotransporter 2 inhibitor, normalizes renal susceptibility to type 1 cardiorenal syndrome through reduction of renal oxidative stress in diabetic rats. PG - 933-946 LID - 10.1111/jdi.13009 [doi] AB - 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 beta-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 beta-hydroxybutyrate levels before MI were inversely correlated with neutrophil gelatinase-associated lipocalin protein levels in OLETF. Pre-incubation with beta-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 beta-hydroxybutyrate-mediated reduction of NOXs and oxidative stress, in type 2 diabetic rats. CI - (c) 2019 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd. FAU - Kimura, Yukishige AU - Kimura Y 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 - Sato, Tatsuya AU - Sato T AD - Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan. AD - Department of Cellular Physiology and Signal Transduction, 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 - Shibata, Satoru AU - Shibata S 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 - Sugawara, Hirohito AU - Sugawara H 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 - Igaki, Yusuke AU - Igaki Y 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 - Miki, Takayuki AU - Miki T AUID- ORCID: 0000-0002-3104-4925 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. LA - eng GR - Mitsubishi Tanabe Pharma Corporation/ GR - 2017-2018/Sapporo Medical University/ PT - Journal Article DEP - 20190225 PL - Japan TA - J Diabetes Investig JT - Journal of diabetes investigation JID - 101520702 RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0SAC974Z85 (Canagliflozin) SB - IM MH - Acute Kidney Injury/etiology/*prevention & control MH - Animals MH - Canagliflozin/*pharmacology MH - Cardio-Renal Syndrome/etiology/*prevention & control MH - Diabetes Mellitus, Type 2/*complications MH - Lipid Peroxidation/drug effects MH - Male MH - Myocardial Infarction/etiology/*prevention & control MH - Oxidative Stress/*drug effects MH - Rats MH - Rats, Inbred OLETF MH - Sodium-Glucose Transporter 2 Inhibitors/*pharmacology PMC - PMC6626958 OTO - NOTNLM OT - Cardiorenal syndrome OT - Oxidative stress OT - Sodium-glucose cotransporter 2 inhibitor EDAT- 2019/01/22 06:00 MHDA- 2020/01/14 06:00 PMCR- 2019/07/01 CRDT- 2019/01/22 06:00 PHST- 2018/10/24 00:00 [received] PHST- 2019/01/12 00:00 [revised] PHST- 2019/01/17 00:00 [accepted] PHST- 2019/01/22 06:00 [pubmed] PHST- 2020/01/14 06:00 [medline] PHST- 2019/01/22 06:00 [entrez] PHST- 2019/07/01 00:00 [pmc-release] AID - JDI13009 [pii] AID - 10.1111/jdi.13009 [doi] PST - ppublish SO - J Diabetes Investig. 2019 Jul;10(4):933-946. doi: 10.1111/jdi.13009. Epub 2019 Feb 25.