Canagliflozin, a Sodium–glucose Cotransporter 2 Inhibitor, Normalizes Renal Susceptibility to Type 1 Cardiorenal Syndrome Through Reduction of Renal Oxidative Stress in Diabetic Rats

Abstract 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.