Abstract
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.
Highlights
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
We previously found that Otsuka Long-Evans Tokushima Fatty rats (OLETF), a model of type 2 DM, showed elevations in AKI markers such as neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) in the kidney after MI without an increase in serum creatinine level[3,4]
Among sham-operated rats, serum creatinine (sCr) level was lower in OLETF than in Long-Evans Tokushima Otsuka rats (LETO) (Fig. 1a), reflecting glomerular hyperfiltration associated with diabetes in this model[3,4,14]
Summary
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. We previously found that Otsuka Long-Evans Tokushima Fatty rats (OLETF), a model of type 2 DM, showed elevations in AKI markers such as neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) in the kidney after MI without an increase in serum creatinine (sCr) level[3,4]. This type of renal injury is consistent with subclinical AKI, defined as a condition in which there is an elevation in AKI markers without an increase in sCr and/or a reduction in urine output in a clinical setting[5,6]. We examined whether empagliflozin attenuates MI-induced AKI in OLETF
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