Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
Department of Pharmacology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Sci Rep. 2020 Apr 29;10(1):7238. doi: 10.1038/s41598-020-64380-y.
Acute kidney injury (AKI) predicts poor prognosis in patients with acute myocardial infarction (MI) and diabetes mellitus (DM) is an independent risk factor of AKI. Recent clinical studies have shown the beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on cardiovascular and renal outcomes in patients with DM. We recently reported that canagliflozin normalized susceptibility of diabetic rats to AKI after acute MI via β-hydroxybutyrate-mediated suppression of NOX expression. Here we examined whether the same renoprotective effect is shared by empagliflozin. Serum creatinine levels were not changed by MI induced by coronary artery occlusion in LETO, non-diabetic control rats, and OLETF, obese type 2 diabetic rats. However, immunohistochemistry revealed that MI increased renal expression of NGAL and KIM-1, early markers of tubular injury, by 3.2-fold and 2.6-fold, respectively, in OLETF. These increases in injury markers were not observed in LETO. Pretreatment with empagliflozin of OLETF for 2 weeks improved hyperglycemia, increased blood β-hydroxybutyrate level, and suppressed MI-induced expression of NGAL and KIM-1. Empagliflozin suppressed upregulation of NOX2 and NOX4 in the kidney of OLETF. Taken together with the results of our previous study, it was concluded that treatment with the SGLT2 inhibitor protects the diabetic kidney from MI-induced AKI.
急性肾损伤（AKI）预测急性心肌梗死（MI）和糖尿病（DM）患者预后不良，是 AKI 的独立危险因素。最近的临床研究表明，钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂对糖尿病患者的心血管和肾脏结局有益。我们最近报道，坎格列净通过β-羟丁酸介导的 NOX 表达抑制使糖尿病大鼠对急性 MI 后 AKI 的易感性正常化。在这里，我们检查了恩格列净是否具有相同的肾脏保护作用。在 LETO 非糖尿病对照大鼠和 OLETF 肥胖 2 型糖尿病大鼠中，冠状动脉闭塞引起的 MI 并未改变血清肌酐水平。然而，免疫组织化学显示，MI 使 OLETF 肾脏中 NGAL 和 KIM-1 的表达分别增加了 3.2 倍和 2.6 倍，这是肾小管损伤的早期标志物。在 LETO 中未观察到这些损伤标志物的增加。OLETF 用恩格列净预处理 2 周可改善高血糖，增加血液β-羟丁酸水平，并抑制 MI 诱导的 NGAL 和 KIM-1 的表达。恩格列净抑制了 OLETF 肾脏中 NOX2 和 NOX4 的上调。综合我们之前的研究结果表明，SGLT2 抑制剂的治疗可保护糖尿病肾脏免受 MI 引起的 AKI。
