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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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Background We recently reported that upregulated AMP deaminase (AMPD), via reduction in the tissue adenine nucleotide pool, contributes to exacerbation of diastolic dysfunction under pressure overload in OLETF, a rat model of obese type 2 diabetes (T2DM). Upregulated AMPD also possibly promotes xanthine oxidase (XO)-mediated ROS production, since AMPD deaminases AMP to IMP, which is further converted to inosine, providing substrates of XO, hypoxanthine and xanthine. Here, we examined the hypothesis that inhibition of XO ameliorates the pressure overload-induced diastolic dysfunction by suppression of ROS-mediated mitochondrial dysfunction and/or vascular dysfunction in T2DM rats. Methods and results Metabolomic analyses revealed that levels of xanthine and uric acid in the LV myocardium were significantly higher by 37% and 51%, respectively, in OLETF than in LETO, non-diabetic control rats, under the condition of phenylephrine-induced pressure overloading (200–230 mmHg). Myocardial XO activity in OLETF was 57.9% higher than that in LETO, which may be attributed to 31% higher level of inosine, a positive regulator of XO, in OLETF than in LETO. The activity of XO was significantly attenuated by administration of topiroxostat, an XO inhibitor at 0.5 mg/kg/day for 14 days. Pressure volume loop analyses showed that the pressure overloading resulted in significantly higher LVEDP in OLETF than in LETO (18.3±1.5 vs. 12.2±1.3 mmHg, p<0.05, n=7), though LVEDPs at baseline were comparable in OLETF and LETO (5.6±0.4 vs. 4.7±0.7 mmHg). Treatment with topiroxostat significantly suppressed the pressure overload-induced elevation of LVEDP in OLETF (18.3±1.5 vs. 11.3±1.1 mmHg, p<0.05) but not in LETO. Under the condition of pressure overloading, Ea/Ees, an index for ventricular-arterial coupling, was higher in OLETF than in LETO (2.3±0.3 vs. 1.6±0.3, p<0.05), and it was also improved by topiroxostat in OLETF (1.2±0.2, p<0.05). Myocardial ATP content was lower in OLETF than in LETO (2966±400 vs. 1818±171 nmol/g wet tissue, p<0.05), and treatment with topiroxostat significantly restored the ATP level (2629±307 nmol/g wet tissue). The LV myocardium of OLETF under pressure overload showed significantly higher level of malondialdehyde and 4-hydroxynonenal, an indicator of lipid peroxidation, than that of LETO. Measurement of oxygen consumption rate by Seahorse XFe96 Analyzer in mitochondria isolated from LV tissues revealed that state 3 respiration was significantly suppressed in OLETF by 43% compared to LETO, and it was restored by treatment with topiroxostat. Conclusion Both activity and substrates of XO are increased in T2DM hearts, in which upregulation of AMPD may play a role. Inhibition of XO ameliorates pressure overload-induced diastolic dysfunction and improves ventricular-arterial coupling in diabetic hearts, most likely through protection of mitochondrial function from ROS-mediated injury. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Grant-in-aid for Scientific Research (#26461132, #17K09584) from the Japanese Society for the Promotion of Science

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